Barbituric acid derivatives, processes for their production and pharmaceutical agents containing these compounds

ABSTRACT

Compounds of formula I, useful as matrix metalloprotease inhibitors, ##STR1## wherein X, Y and Z are each oxygen; 
     R 1  is selected from the group consisting of (a) n-octyl, (b) n-decyl, (c) biphenyl and (d) (4-phenoxy)phenyl, wherein the terminal monocycle for moieties (c)-(d) is unsubstituted or substituted by a substituent selected from the group consisting of --NH 2 , --NO 2 , --SO 2  NH 2 , --SO 2  CH 3 , acetyl, hydroxy, methoxy, ethoxy, cyano and halogen; 
     R 2  and R 3  are each hydrogen; and 
     R 4  and R 5 , together with the nitrogen atom to which they are bound, form a piperazinyl or piperidyl ring, wherein the piperazinyl ring is substituted in the 4-position with a substituent selected from the group consisting of (a) a 6-membered aromatic monocycle having 0, 1 or 2 nitrogen atoms and the remainder of the atoms in the monocycle being carbon and (b) hydroxy-C 1  -C 6  alkyl, wherein the monocycle is unsubstituted or substituted by a substituent selected from the group consisting of halogen, --NH 2 , --NO 2 , --SO 2  NH 2 , --SO 2  CH 3 , acetyl and cyano.

This application is a 371 of PCT/EP96/05766.

In normal tissue there is an equilibrium between synthesis anddegradation. Extracellular matrix is degraded by proteases which belongto at least three groups of matrix metalloproteases. These are thecollagenases, geiatinases and stromelysins. Normally there are specificinhibitors for these catabolic enzymes such as α₂ macroglobuhnes and MMP(=tissue inhibitor of metalloproteases (MMP)) so that an excessivedegradation of extraceilular matrix does not occur. A related group ofproteases is the adamalysins. A prominent member of the adamalysins isTACE (TNF-α-converting enzyme).

At least 11 different and yet highly homologous MMP species have beencharacterized, including the interstitial fibroblast collagenase (MMP-1,HFC), the neutrophil collagenase (MMP-8, HNC), two gelatinases,stromelysins (such as HSL-1) and HPUMP (for a recent review, seeBirkedal-Hansen, H., Moore, W. G. I., Bodden, M. K., Windsor, L. J.,Birkedal-Hansen, B., DeCarlo, A., Engler, J. A., Critical Rev. OralBiol.Med. (1993) 4, 197-250. These proteinases share a number ofstructural and functional features but differ somewhat in theirsubstrate specificity. Only HNC and HFC are capable of cleaving type I,II and III native triple-helical collagens at a single bond with theproduction of fragments 3/4 and 1/4 of the native chain length. Thislowers the collagen melting point and makes them accessible to furtherattack by other matrix degrading enzymes.

However, the uncontrolled excessive degradation of this matrix is acharacteristic of many pathological states such as e.g. in the clinicalpicture of rheumatoid arthritis, osteoarthritis, multiple sclerosis, inthe formation of tumour metastases, corneal ulceration, inflamativediseases and invasion and in diseases of the bone and teeth.

It can be assumed that the pathogenesis of these clinical pictures canbe favourably influenced by the administration of matrix metalloproteaseinhibitors. A number of compounds in the meantime are known in theliterature (see e.g. the review article of Nigel RA Beeley et al. Curr.Opin. ther. Patents 4 (1), 7 (1994)) or are described in the patentliterature, these mainly being peptides with a hydroxamic acid residue,a thiol or phosphine group as a zinc binding group (see e.g.WO-A-9209563 by Glycomed, EP-A-497 192 by Hoffmann-LaRoche. WO-A-9005719by British Biotechnology, EP-A-489 577 by Celitech. EP-A-320 118 byBeecham, U.S. Pat. No. 4,595,700 by Searle among others).

Some of these compounds have a high activity as inhibitors of matrixmetalloproteases but only have a very low oral availability.

It has now been found that the claimed new barbituric acid derivativesare very efficacious as matrix metallo-protease inhibitors and have agood oral availability.

The present invention therefore concerns substances of the generalformula I ##STR2## in which X, Y and Z are independently of one anotheroxygen sulphur or NH,

R₁ represents a group W-V

W is a valence dash or a straight-chained or branched C₁ -C₈ alkyl or aC₂ -C₈ alkenyl group which is optionally once or several timessubstituted,

V is an optionally substituted monocycle or bicycle which can containone or several heteroatoms,

or

W-V is a C1-20 akyl group which can be interrupted by heteroatoms, oneor several carbon atoms are optionally substituted,

R₂ and R₃ represent hydrogen or one of the two represents lower alkyl orlower acyl

R₄ and R₅ denote independently of each other for A-D wherein Arepresents a dash alkyl, alkenyl, acyl, alkylsulfonyl, sulfonyl,alkylaminocarbonyl, arninocarbonyl, alkoxycarbonyl, oxy-carbonyl,alkylaminothiocarbonyl, aminothio-carbonyl which is optionally once orseveral times substituted,

D represents a hydrogen, mono or bicycle, the monocycle or bicycle isoptionally once or several times interrupted by heteroatoms and themonocycle or bicycle is once or several times substituted,

or

R₄ and R₅ together with the nitrogen atom to which they are boundrepresent a ring which optionally can be interrupted by a further Natom, said ring can be condensed to a monocycle or bicycle, said ringcan optionally be substituted once or several times independently by theresidues hydroxy, alkoxy, amino, alkylamino, dialkylamino, nitril or byE-G wherein E represents a dash, alkyl, alkenyl, acyl, alkylsulfonyl,sulfonyl, alkylarinocarbonyl, aminocarbonyl, alkoxycarbonyl,oxy-carbonyl, alkylaminothiocarbonyl, aminothiocarbonyl which isoptionally substituted; G represents a hydrogen, mono or bicycle, themonocycle or bicycle is optionally once or several times interrupted byheteroatoms and the monocycle or bicycle is once or several timessubstituted,

pharmacologically acceptable salts or prodrugs thereof as well as theuse of these compounds to produce pharmaceutical agents.

The monocycle listed in the case of R₁, R₄ and R₅ is understood assaturated or unsaturated ring systems with 3-8, preferably 5-7 carbonatoms which can optionally be interrupted one or several times byheteroatoms such as nitrogen, oxygen or sulphur in particular acyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl,piperidinyl, piperazinyl, tetrahydrofliranyl, tetrahydropyranyl, phenyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl,imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl or 1,2,4-triazolyl residue. Lower alky, alkoxy andhalogen come above all into consideration as substituents. The bicyclelisted under R₁, R₄ and R₅, is understood to be a condensed bicycle or abicycle of the type monocycle₁ -L-monocycle₂, wherein L denotes avalence dash C₁ -C₄ -alkyl group, C₂ -C₄ an alkenyl group, an oxygen or--C(O)-group.

The bicycle is preferably a residue such as a naphthyl,tetrahydronaphthyl, dekalinyl, quinolinyl, isoquinoiinyl,tetrahydroquino-linyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxazolyl, purinyl, biphenyl or (4-phenoxy)phenyl residue and inparticular a naphthyl, biphenyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, indolyl or benzimnidazolyl residue.

The residues listed under R₁, R₄ and R₅ can optionally be substitutedonce or several times by halogen, hydroxy, thio, alkyl, hydroxyalkyl,alkoxy, alkylhio, alkylsulfinyl, alkyl-sulfonyl, amino, alkylamino,dialkylamino, nitro, carboxyl, carboxamido, alkoxycarbonyl, amino oraminocarbonyl optionally substituted once or twice by lower alkyl,nitrile, oxo, thiocarboxamido, alkoxythiocarbonyl, alkmercaptocarbonyl,phosphono, alkylphosphono, dialkylphosphono, alkylsulfonylamido,arylamino, aryl, hetaryl, aryloxy, arylthio, arylsulfinyl, arylsulfonylor acyl.

In this case the halogen, hydroxy, oxo, thio, alkoxy, alkylthio, amino,aminocarbonyl, carboxyl and acyl groups are preferred.

Lower alkyl denotes C₁ -C₆ -Alkyl, preferred methyl, ethyl, propyl,isopropyl or tert-butyl.

Lower acyl in the residues R₂ and R₃ above all denotes for --C(O)-C₁ -C₆-alkyl or --C(O)H, preferred for an acetyl group.

The alkyl residues in R₁, R₄ and R₅ can optionally be interrupted onceor several time by heteroatoms (O, S, NH).

Alkyl in the residues R₄ and R₅ denotes as such or in combination withalkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylaminocarbonyl,arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl,alkylaminothiocarbonyl, arylamnlothiocarbonyl a straight-chained,branched, saturated or unsaturated residue with 1-11, preferably 1-8carbon atoms such as e.g. a methyl, ethyl, propyl, pentyl, octyl, allyl,propargyl, 2,4-pentadienyl, isopropyl, sec. butyl, 3-methylbutyl,2-hydroxyhexyl and in particular a methyl, propyl, isopropyl, pentyl,octyl, allyl, 3-methylbutyl, 2-hydroxyhexyl and propargyl residue.

Aryl, also in combination with aryloxy, arylthio, arylsulfonyl,arylaminocarbonyl, aryloxycarbonyl, arylaminothiocarbonyl is understoodas a phenyl or naphthyl residue which can optionally be substituted inparticular by halogen, lower alkyl or alkoxy.

The C₁ -C₂₀ alkyl group listed for R₁ is a straight-chained or branchedsaturated residue such as e.g. a methyl, ethyl, propyl, butyl, pentyl,octyl, decyl, undecyl, isobutyl, 3-methylbutyl or 7-methyloctyl group.Hydroxy and amino residues come above all into consideration assubstituents. The alkyl chains can be interrupted once or several timesby oxygen, nitrogen or sulphur. The preferred heteroatom interruption isoxygen (ether linkage) or --C(O)NH-- (amid linkage). The most preferredheteroatom interrupted residues are --(CH₂ CH₂ O)_(n) --(CH₂)_(m) H andn=2 or 3 and m=1 or 2.

W of R₁ is preferrably a methyl, ethyl, butyl or hexyl residue; V is inparticular a phenyl, Pyridyl, imidazolyl residue which can optionally besubstituted above all by lower alkyl, hydroxy, alkoxyamid, suifonamideor halogen. The most preferred R1 residues are C6-C12-Alkyl residue or a--(CH₂)_(n) --C₆ H₄ --(CH₂)_(m) H residue, wherein m and n are equal orless than 8, the (CH₂)-group is optionally interrupted by oxygen,sulfur, or NH and one or two carbons of the phenyl ring are substitutedfor N-heteroatoms. The alkyl, aryl, hetaryl groups are optionallysubstituted by small polar substituents.

The most preferred R₁ residues are n-Octyl, n-Decyl, Biphenyl or octylor decyl type residues showing two or three oxygen heteroatoms like2-(2-(2-methoxyethoxy)ethoxy)ethyl, 2-(2-ethoxyethoxy)ethyl orbiphenyl-type residues showing one or two nitrogen heteroatoms. Thebridging monocycle is optionally ortho substituted and the terminalmonocycle of the biphenyl or biphenyl type residue is optionally orthoor para substituted by a small, polar substituent like NH₂, --NO₂, --SO₂NH₂, SO₂ CH₃, Acetyl, Hydroxy, Methoxy, Ethoxy or Nitril-group. The parasubstitution of the terminal monocycle is more preferred.

Halogen is understood as chlorine, bromnine, iodine and preferablychlorine.

The hetaryl residues listed for R₄ and R₅ denote preferred for apyridine, pyrazine, piperazine, imidazole, thiazole, thiophene or indolering preferably a pyridine, imidazole and thiophene ring.

The acyl residue listed for the residues R₄ and R₅ is a residue with1-10, preferably 6-8 carbon atoms such as e.g. a hexanoyl or octanoylresidue. The alkyl group can be interrupted once or several times byheteroatoms or heteroatom groups like S, O, NH, SO₂, amido or carbonyl.These residues can be substituted by amino groups, alkyl groups, arylgroups, arylalkyl groups, alkylamino groups, dialkylamino groups, alkoxygroups and aromatic compounds. These are then amino acid residuespreferably a phenylalanine and tryptophan residue in this case.

If R₄ and R₅ form a ring together with the nitrogen atom to which theyare bound, these are 5-7-membered rings preferably a six-membered ring.The piperidine, piperazine, tetrahydroquinoline andtetrahydroiso-quinoline, bicyclo(9.4.0)pentadecyl and1,2,3,4-tetrahydrobenzo(g)isoquinoline rings are preferred.

If compounds of the general formula I contain one or several asymmetriccarbon atoms, the optically active compounds of the general formula Iare also a subject matter of the present invention.

Independently of each other the preferred meaning for X, Y, Z is oxygen,for R₂ and R₃ it is hydrogen. A more preferred combination is X, Y and Zequal each oxygen and R₂ is identical to R₃ and both mean hydrogen.

It is also preferred that R₄ and R₅ do not both represent hydrogen.

The term "several" means in connection with heteroatoms in monocycles orbicycles preferred one, two or three more preferred one or two, the mostpreferred heteroatom is nitrogen.

The term "several" means in connection with substituents or substitutionpreferred one to five, more preferred one, two or three most preferredone or two. The term "heteroatom" in connection with alkyl or acylgroups means preferred oxygen or NH, more preferred oxygen.

Substitutions of monocycles or bicycles in R₁, R₄ and R₅ are halogen,nitro, hydroxy, alkoxy, amino, alkylamino, dialkylamino, halogenmethyl,dihalogenmethyl, trihalogenmethyl, phosphono, alkylphosphono,dialkylphosphono, SO₂ NH₂, SO₂ NH(alkyl), SO₂ N(alkyl)₂, SO₂ (alkyl),acetyl, formyl, nitril, COOH, COOalkyl, --OC(O)alkyl, --NHC(O)Oalkyl,OC(O)O-aryl, --NHC(S)NH₂, --NHC(S)NHalkyl, --NHC(O)-aryl.

The preferred ring structure formed together with the nitrogen, R₄ andR₅, is piperazin or piperidin, both of which are substituted preferrablyat the 4-position. In the case of piperidin the 4 position is optionallysubstituted by a second substitute hydroxy, amino, alkylamino,alkylamino, dialkylamino or alkoxy. The 4 position of piperidin may alsoform a double bond with the substituent of the 4 position.

Preferred substitution of the 4 position of piperidin or piperazin are6-membered aromatic monocycles which are more preferred substituted inpara position by small polar substitutions as hydroxy, lower alkoxy,amino, lower alkylamino, lower dialkylamino, nitro, nitrilo, SO₂ NH₂,SO₂ NH lower alkyl, SO₂ lower alkyl. The 6 membered aromatic monocycleis preferrably bound to the 4 position via a valence bond or a loweralkyl spacer.

In the case that R₄, is hydrogen a lower alkyl a lower alkylaryl, thenR₅ is preferred a acyl derivate preferrably substituted with a monocyleor lower alkylaryl; or a --CHR₅₀ --CHR₅₁ --NR₅₂ --R₅₃ wherein R₅₀ andR₅₁ denote independently of each other for hydrogen, lower alkyl a loweralkoxy. R₅₂ denotes for hydrogen or lower alkyl, R₅₃ denotes a6-membered aromatic monocycle which is optionally once or several timessubstituted and bound to the nitogen preferrably via a valence bond or alower alkyl spacer.

The most preferred combination of meanings in general formula I are

X equals Y equals Z equals oxygen and

R₂ equals R₃ equals hydrogen and

R₁ equals n-Octyl, n-Decyl, Biphenyl or octyl or decyl type residuesshowing two or three oxygen heteroatoms like2-(2-(2-methoxyethoxy)-ethoxy)ethyl, 2-(2-ethoxyethoxy)ethyl orbiphenyl-type residues showing one or two nitrogen heteroatoms; whereinthe bridging monocycle is optionally ortho substituted and the terminalmonocycle of the biphenyl or biphenyl type residue is optionally orthoor preferred para substituted by a small, polar substituent like NH₂,--NO₂, --SO₂ NH₂, SO₂ CH₃, Acetyl, Hydroxy, Methoxy, Ethoxy orNitril-group and

R₄ and R₅ form together with the nitrogen to which they are bound apiperazin or piperidin both of which are substituted in the 4 positionwith a phenyl, pyridyl or pyrazidyl ring which is preferred parasubstituted by a small polar substituent; in the case of piperidin the 4position may be additionally sustituted by hydroxy, lower alkoxy, nitrilor amin which may be mono- or disubstituted by lower alkyl.

Compounds of the general formula I can be synthesized by well-knownprocesses preferably in that

a) compounds of the general formula II ##STR3## in which X, Y, Z, R₁, R₂and R₃ have the above-mentioned meanings and T represents a leavinggroup such as Hal or OSO₂ R₆ Hal denoting chlorine, bromine or iodineand R₆ denoting an aryl or a methyl residue, are reacted with a compoundof the general formula III ##STR4## in which R₄ and R₅ have the meaningsstated above and optionally converted into pharmacologically acceptablesalts or

b) compounds of the general formula IV ##STR5## in which R₁, R₄ and R₅have the above-mentioned meanings, Y and Z independently of one anotherrepresent oxygen, sulphur or a NH group and R₇ =methyl, ethyl or phenyl,is reacted with a compound of the general formula V ##STR6## in whichR₂, R₃ and X have the above-mentioned meanings and optionally convertedinto pharmacologically acceptable salts

or

n the case that R₄ and/or R₅ represent an acyl, alkylsulfonyl,arylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminothiocarbonyl or arylaminothiocarbonyl residue

c) a compound of the general formula VI ##STR7## in which X, Y, Z, R₁,R₂ and R₃ have the above-mentioned meanings, is reacted with a compoundof the general formula VII or VIII

    R.sub.8 --D--Hal                                           (VII)

    R.sub.8 N═C═A                                      (VIII)

in which R₈ represents an optionally substituted alkyl or aryl residue,D═C(O), O--C(O), SO₂ or a valency dash. Hal=chlorine, bromine or iodineand A represents oxygen or sulphur

and optionally converted into pharmacologically acceptable salts.

Compounds of the general formula II are known in the literature. Thusfor example 2,4,6-pyrimidine triones brominated in the 5-position can besynthesized by reacting the appropriate bromomalonic acid dialkyl esterswith urea (e.g. Acta Chim. Acad. Sci. Hung. 107 (2), 139 (1981)). Thecorresponding brominated or chlorinated compounds of the general formulaII can be obtained by reacting 2,4,6-pyrimidine-triones substituted byR₁ in the 5-position with bromine (analogous to J. pr. Chemie 136, 329(1933) or J. Chem. Soc. 1931, 1870) or sulfuryl chloride (J. Chem. Soc.1938, 1622). In the same manner one can synthesize the2-imino-4,6-pyrimidine-diones of the general formula II correspondinglyhalogenated in the 5-position analogously to Collect. Czech. Comm. 48(1), 299 (1933). The reaction of 2-thia-4,6-pyrinidine-dionessubstituted by R₁ in the 5-position with bromine in glacial acetic acid(analogously to Am. Chem. J. 34, 186) leads to the compounds of thegeneral formula II correspondingly brominated in the 5-position.

Amines of the general formula III are commercially available or areusually known in the literature.

Compounds of the general formula IV are reacted according to knownmethods with ureas (see for example J. Med. Chem. 10, 1078 (1967) orHelvetica Chim. Acta 34, 459 (1959) or Pharmacie 38 (1), 65 (1983)),thioureas (see for example Indian J. Chem. 24 (10), 1094 (1985) or J.Het. Chem. 18 (3), 635 (1981)) or guanidines (see for example Collect.Czech. Chem. Comm. 45 (12), 3583 (1980)) of the general formula V.

The reactions are usually carried out in an alcohol such as methanol,ethanol or butanol in the presence of an appropriate sodium alcoholateat temperatures between 40° C. and 100° C. and in the case of theguanidines also at temperatures of up to 200° C. (under pressure). Inthe case of the thioureas the process is frequently carried out in thepresence of acetyl chloride (also as a solvent).

Compounds of the general formula IV are known from the literature or canbe produced according to processes known from the literature. They canbe synthesized for example by weak acidic hydrolysis of thecorresponding bislactim ethers (see J. Chem. Soc. Chem. Comm. 5, 400(1990)). Other methods of synthesis are for example described in FarmacoEd. Sci. 31 (7), 478 (1976) or Aust. J. Chem., 23 (6), 1229 (1970).

Ureas, thioureas and guanidines of the general formula V arecommercially available.

Compounds of the general formula VI can easily be synthesized byreacting an appropriate substituted acetamidomalonic ester according toprocess b) and subsequent hydrolytic cleavage of the acetyl group (seeCan. J. Chem. 42 (3), 605 (1964)).

Carboxylic acid chlorides of the general formula VII are known or can besynthesized by generally known methods from the corresponding carboxylicacids. The reaction is usually carried out with thionyl chloride orphosphorus tribromide or phosphorus pentabromide or pentachloride ininert solvents such as dichloromethane, diethyl ether, dioxane ortetrahydrofuran at temperatures of 0° C. to 50° C., preferably between20° C. and 40° C.

Chloroformic acid esters of the general formula VII are known in theliterature or can be obtained by generally known methods from thecorresponding alcohols by reaction with. phosgene or diphosgene. Thereaction proceeds in inert solvents such as e.g. diethyl ether,dichloromethane, dioxane, tetrahydrofuran or toluene at temperaturesbetween -20° C. and 20° C. In the case of phosgene the reaction iscarried out in the presence of bases, usually tertiary amines such ase.g. triethylamine or pyridine.

Sulfonic acid chlorides of the general formula VII are known or can besynthesized analogously to described methods from the correspondingsulfonic acids by reaction with phosphorus pentachloride or thionylchloride. The reaction is usually carried out in an inert solvent suchas e.g. dimethylformamide or also without a solvent at temperatures of20° C. to 180° C., preferably at 50° C. to 100° C.

Isocyanates of the general formula VIII are known or can be synthesizedby methods known in the literature. Thus for example appropriate alkylhalogenides of the general formula R₈ -Hal can be reacted with potassiumcyanate analogously to Synthesis 1978, 760. Further methods are to reactan acid amide of the general formula R₈ --CONH₂ with oxalyl chloride, tothermally decompose an acid azide of the general formula R₈ --CON₃ or toreact an amine of the general formula R₈ --NH₂ with phosgene(analogously to Ann. Chem. 562, 110).

Isothiocyanates of the general formula VIII are known in the literatureor can be synthesized analogously to known processes. An amine of thegeneral formula R₈ --NH₂ is preferably allowed to react with carbondisulphide under alkaline conditions analogously to Chem. Ber. 74, 1375.

The reaction of carboxylic acid halogenides, sulfonic acid halogenidesor chloroformic acid esters of the general formula VII with amines ofthe general formula VI is usually carried out in a solvent such asdichloromethane, dimethylformamide or pyridine with addition of anauxiliary base such as triethylamine or 4-dimethylaminopyridine at atemperature between -10° C. and 50° C. preferably at room temperature.

Compounds of the general formula I can contain one or several chiralcentres and can then be present in a racemic or in an optically activeform. The racemates can be separated according to known methods into theenantiomers. Preferably diastereomeric salts which can be separated bycrystallization are formed from the racemic mixtures by reaction with anoptically active acid such as e.g. D- or L-tartaric acid, mandelic acid.malic acid, lactic acid or camphorsulfonic acid or with an opticallyactive amine such as e.g. D- or L-α-phenyl-ethylamine, ephedrine,quinidine or cinchonidine.

Alkaline salts, earth alkaline salts like Ca or Mg salts, ammoniumsalts, acetates or hydrochlorides are mainly used as pharmacologicallyacceptable salts which are produced in the usual manner e.g. bytritrating the compounds with inorganic or organic bases or inorganicacids such as e.g. sodium hydroxide, potassium hydroxide, aqueousammnonia, C₁ -C₄ -alkyl-armines such as e.g. triethylamiine orhydrochloric acid. The salts are usually purified by reprecipitationfrom water/acetone.

The new substances of formula I and salts thereof according to theinvention can be administered eternally or parenterally in a liquid orsolid form. In this connection all the usual forms of administrationcome into consideration such as for example tablets, capsules, coatedtablets, syrups, solutions, suspension etc. Water which containsadditives such as stabilizers solubilizers and buffers that are usual ininjection solutions is preferably used as the injection medium.

Such additives are e.g. tartrate and citrate buffer, ethanol, complexingagents (such a ethylenediaminetetra-acetic acid and non-toxic saltsthereof), high-molecular polymers (such as liquid polyethylene oxide) toregulate viscosity. Liquid carrier substances for injection solutionshave to be sterile and are preferably dispensed into ampoules. Solidcarrier substances are e.g. starch, lactose, mannitol, methylcellulose,talcum, highly dispersed silicic acids, higher molecular fatty acids(such as stearic acid), gelatins, agar-agar, calcium phosphate,magnesium stearate, animal and vegetable fats, solid high-molecularpolymers (such as polyethylene glycols); suitable preparations for oralapplication can optionally also contain flavourings and sweeteners.

The dosage can depend on various factors such as manner ofadministration, species, age and/or individual state of health. Thedoses to be administered daily are about 10-1000 mg/human, preferably100-500 mg/human and can be taken singly or distributed over severaladministrations.

Prodrugs of the compounds of the invention are such which are convertedin vivo to the pharmacological active compound. The most common prodrugsare carboxylic acid esters.

Within the sense of the present invention the following barbituric acidderivatives are preferred in addition to the compounds mentioned in theexamples and compounds that can be derived by combining all meanings ofsubstituents mentioned in the claims:

1. 5-(N-benzyl-N-octyl)-5-phenyl-barbituric acid

2. 5-(N-benzyl-N-phenethyl)-5-phenyl-barbituric acid

3. 5-(N-benzyl-N-[2-(4-pyrdyl)ethyl)]-5-phenyl-barbituric acid

4. 5-(N-benzyl-N-[2-(3-pridyl)ethyl]-5-phenyl-barbituric acid

5. 5-(N-benzyl-N-[2-(2-pridyl)ethyl]-5-phenyl-barbituric acid

6. 5-(N-benzyl-N-[2-(2-thiophenyl)ethyl]-5-phenyl-barbituric acid

7. 5-[N-(3-methylbutyl)-N-(3-phenylpropyl)]-5-phenyl-barbituric acid

8. 5-(N-benzyl-N-[3-(4-pyridyl)propyl])-5-phenyl-barbituric acid

9. 5-(N-benzyl-N-[2-(2-imidazolyl)ethyl])-5-phenyl-barbituric acid

10. 5-(N-benzyl-N-[2-(1-imidazolyl)ethyl])-5-phenyl-barbituric acid

11. 5-(N-butyl-N-phenylalaninyl)-5-phenyl-barbituric acid

12. 5-(N-butyl-N-tryptophanyl)-5-phenyl-barbituric acid

13. 5-(N-benzyl-N-cyclohexyl)-5-phenyl-barbituric acid

14. 5-[N-benzyl-N-(2-priridyl)]-5-phenyl-barbituric acid

15. 5-[N-butyl-N-(4-pipendyl)]-5-phenyl-barbituric acid

16. 5-[N-benzyl-N-(2-imidazolyl)]-5-phenyl-barbituric acid

17. 5-(N-octyl-N-phenyl)-5-phenyl-barbituric acid

18. 5-[N-(2-naphthyl)-N-propyl]-5-phenyl-barbituric acid

19. 5-[N-(4-tetrahydroquinolinyl)-N-propyl]-5-phenyl-barbituric acid

20. 5-[N-benzyl-N-(2-thiophenyl)]-5-phenyl-barbituric acid

21. 5-[N-(3-methylbutyl)-N-[3-(4-pyridyl)propyl)]-5-phenyl-barbituricacid

22. 5-[N-(7-methyyloctyl)-N-[3-(2-pyridyl)propyl)]-5-phenyl-barbituricacid

23. 5-(N-(2-hydroxyhexyl)-N-[3-(3-pyridyl)propyl])-5-phenyl-barbituricacid

24. 5-(N-benzyl-N-hexanoyl)-5-phenyl-barbituric acid

25. 5-(N-benzyl-N-octanoyl)-5-phenyl-barbituric acid

26. 5-(N-benzyl-N-octanesulfonyl)5-phenyl-barbituric acid

27. 5-[N-butyl-N-(2-naphthylsulfonyl)]-5-phenyl-barbituric acid

28. 5-(N-hexyloxycarbonyl-N-propyl)-5-phenyl-barbituric acid

29. 5-(N4-methoxy-phenylsulfonyl)-N-hexyl]-5-phenyl-barbituric acid

30. 5-[N-(4-butoxy-phenylsuifonyl)]-N-hexyl]-5-phenyl-barbituric acid

31. 5-[N-benzyl-N-(2-phenethyl)]-5-(4-pyridyl) barbituric acid

32. 5-[N-benzyl-N-(2-phenethyl)]-5-(2-pyridyl) barbituric acid

33. 5-(N,N-dipentyl)-5-(4-piperidinyl)barbituric acid

34. 5-(N,N-dioctyl)-5-(2-thiophenyl)barbituric acid

35. 5-(N-benzyl-N-[2-(2-pyridyl)ethyl]-5-3-imidazolyl) barbituric acid

36. 5-[1-(4-hydroxy)piperidinyl]-5-(4-pyridyl) barbituric acid

37. 5-[1-(4-hydroxy)piperidinyl]-5-(3-pyridyl) barbituric acid

38. 5-[1-(4-hydroxy)piperidinyl]-5-(2-pyridyl) barbituric acid

39. 5-[1-(4-hydroxy)piperidinyl]-5-(4-piperidinyl) barbituric acid

40. 5-[1-(4-hydroxy)piperidinyl]-5-(2-thiophenyl) barbituric acid

41. 5-[1-(4-hydroxy)piperidinyl]-5-(4-imidazolyl) barbituric acid

42. 5-benzyl-5-[1-(4-hydroxy)piperidinyl]barbituric acid

43. 5-[1-(4-hydroxy)piperidinyl]-5-(2-phenethyl) barbituric acid

44. 5-[1-(4-hydroxy)piperidinyl]-5-(1-naphthyl) barbituric acid

45. 5-[1-(4-hydroxy)piperidinyl]-5-(2-naphthyl) barbituric acid

46. 5-(2-quinolinyl)-5-[1-(4-hydroxy)piperidinyl] barbituric acid

47. 5-[1-(4-hydroxy)piperidinyl]-5-(1-isoquinolinyl) barbituric acid

48. 5-[1-(4-hydroxy)piperidinyl]-5-(2-tetraydro-quinolinyl)barbituricacid

49. 5-(2-indolyl)-5-[1-(4-hydroxy)piperidinyl] barbitric acid

50. 5-(2-benzimidazolyl)-5-[1-(4-hydroxy)piperidinyl] barbituric acid

51. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-octyl-barbituric acid

52. 5-decyl-5-(1-[4-(2-hydroxyethyl)piperazinyl]) barbituric acid

53. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-undecyl-barbituric acid

54. 5-[4-(2-hydroxyethyl)piperazinyl])-5-(7-methyl-octyl)barbituric acid

55. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(8-hydroxy-octyl)barbituricacid

56. 5-(8-aminooctyl)-5-(1-[4-(2-hydroxyethyl) piperazinyl])barbituricacid

57. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(2-phen-ethyl)barbituricacid

58. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(4-phenyl-butyl)barbitunricacid

59. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(6-phenyl-hexyl)barbituricacid

60.5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-[6-(4-methylphenyl)hexyl]barbituricacid

61. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(2-pyridylmethyl)barbituricacid

62.5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(4-imidazolylmetyl)barbituricacid

63.5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(1-imidazolylmethyl)barbituricacid

64. 5-phenyl-5-(1-(4-propyl)piperazinyl]barbituric acid

65. 5-phenyl-5-(1-tetrahydroquinolinyl)barbituric acid

66. 5-phenyl-5-(1-tetrahydroisoquinolinyl)barbituric acid

67. 5-phenyl-5-[2-(1,2,3,4-tetrahydrobenzo(g)iso-quinolinyl]barbituricacid

68. 5-[2-(2-aza-bicycio[9.4.0]pentadecyl)]-5-phenyl-barbituric acid

69.5-[2-(2,11-diaza-12-oxo-bicyclo[9.4.0]pentadecyl)]-5-phenyl-barbituricacid

70. 5-(1-[4-(1-oxo-propyl)]piperidinyl)-5-phenyl-barbituric acid

71. 5-[1-(3-oxo-4-propyl)]piperidinyl]-5-phenyl-barbituric acid

72. 5-phenyl-5-[1-(4-propyl)piperazinyl]barbituric acid

73. 5-[1-(3,5-dihydroxy-4-propyl)piperidinyl]-5-phenyl-barbituric acid

74. 5-(4-chlorophenyl)-5-[1-(4-hydroxy)piperidinyl] barbituric acid

75. 5-(4-chlorobenzyl)-5-[1-(4-hydroxy)piperidinyl] barbituric acid

76. 5-[1-(4-hydroxy)piperidinyl]-5-(4-methoxybenzyl) barbituric acid

77. 3-methyl-5-[1-(4-hydroxy)pipendinyl]-5-phenyl-barbituric acid

78. 1-isopropyl-5-[1-(4-hydroxy)piperidinyl]-5-phenyl-barbituric acid

79. 3-acetyl-5-[1-(4-hydroxy)piperidinyl]-5-phenyl-barbituric acid

80. 5-[1-(4-methoxy)piperidinyl]-5-phenyl-2-thio-barbituric acid

81. 2-imino-5-[1-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid

82. 5-[1-(4-methoxy)piperidinyl]-5-phenyl-2,4,6-triimino-barbituric acid

83. 4,6-diimino-5-[1-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid

84. 5-[1-(4-methoxy)piperidinyl]-5-phenyl-2,4,6-trithio-barbituric acid

85. 5-(6-aminohexyl)-5-[N(2-hydroxyethyl)piperazinyl]barbituric acid

86. 5-(6-formylaminohexyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituricacid

87. 5-(6-acetylaminohexyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituricacid

88.5-[7-(ethoxycarbonyl)heptyl]-5-[N-(2-hydroxyethyl)piperazinyl]barbituricacid

89. 5-(8-hydroxyoctyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid

90. 5-(7-carboxyheptyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid

91.5-[7-(aminocarbonyl)heptyl]-5-[N-(2-hydroxyethyl)piperazinyl]barbituricacid

92.5-[3-((aminocarbonylmethyl)aminocarbonyl)propyl]-5-[N-(2-hydroxyethyl)piperazinyl]barbitunricacid

93. 5-[6-(methylamino)hexyl]-5-[N-(4-nitrophenyl)piperazinyl]barbituricacid

94. 5-[4-(n-propytoxy)butyl]-5-[N-(4-nitrophenyl)piperazinyl]barbituricacid

95. 5-[2-(2-(2-methoxyethoxy)ethoxy)ethyl]-5-[N-(4-3 5nitrophenyl)piperazinyl]barbituric acid

96.5-[2-(2-(ethoxy)ethoxy)ethyl]5-[N-(4-nitrophenyl)piperazinyl]barbituricacid

97. 5-decyl-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid

98. 5-octyl-5-[N-(4-(hydroxysulphonyl)phenyl)piperazinyl]barbituric acid

99. 5-octyl-5-[N-(4-(aminosulphonyl)phenyl)piperazinyl]barbituric acid

100. 5-octyl-5-[N-(4-cyanophenyl)piperazinyl]barbituric acid

101. 5-octyl-5-[N-(4-carboxyphenyl)piperazinyl]barbituric acid

102. 5-octyl-5-[N-(4-(buthoxycarbonyl)phenyl)piperaznyl]barbituric acid

103. 5-octyl-5-[N-(4-(amidino)phenyl)piperazinyl]barbituric acid

104. 5-octyl-5-[N-(4-(aminothiocarbonyl)phenyl)piperaznyl]barbituricacid

105. 5-octyl-5-[N-(4-methylsulphonyl)phenyl)piperazinyl]barbituric acid

106. 5-octyl-5-[N-(4-(aminocarbonyl)phenyl)piperazinyl]barbituric acid

107. 5-octyl-5-[N-(4-(methylcarbonyl)phenyl)piperazinyl]barbituric acid

108. 5-octyl-5-[N-(4-(dimethylphosphonyl)phenyl)piperazinyl]barbituricacid

109. 5-octyl-5-[N-(4-amino)phenyl)pipeyl]barbitric acid

110. 5-octyl-5-[N-(4-acetylamino)phenyl)piperazinyl]barbituric acid

111. 5-octyl-5-[N-(4-(trfluoroacetylamino)phenyl)piperazinyl]barbituricacid

112. 5-octyl-5-[N-(4-(methylsulphonylamino)phenyl)piperazinyl]barbituricacid

113. 5-octyl-5-[N-(5-nitropyrid-2-yl)piperazinyl]barbituric acid

114. 5-octyl-5-[N-(N-oxypyrid 4yl)piperazinyl]barbituric acid

115. 5-octyl-5-[N-(4-(5-triazolyl)phenyl)piperazinyl]barbituric acid

116. 5-octyl-5-[(N-benzoyl-N-benzyl)amino]barbituric acid

117. 5-[4-(phenyl)phenyl]-5-[(N-benzoyl-N-benzyl)amino]barbituric acid

118. 5-(4-[4-Nitrophenyl)piperazinyl])-5-octyl-barbituric acid

119.N-Benzyl-3-(4-nitro-phenyl)-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)-acrylamide

120.N-Benzyl-2-(3-bromo-phenyl)-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)-acetamide

EXAMPLE 1 5-(1-1-([4-2-Hydroxynethyl)piperazinyl)-5-phenyl-barbituricacid

5-Bromo-5-phenyl barbituric acid (Acta Chim. Acad. Sci. Hung. 107 13945(1981)) (7 mmol) and N-(2-hydroxy-ethyl)-piperazine (8 mmol) aresuspended in 40 ml absolute ethanol. After 3 hours under reflux it isconcentrated in a vacuum. The residue is purified by chromatography onsilica gel (ethyl acetate/methanol 3:1). Colourless crystals areobtained by recrystallization from isopropanol. Yield 56%; Fp. 238-40°C. (decomp.).

EXAMPLE 25-(1-[4-(4-Methylphenyl)methyl]piperazinyl]-5-phenyl-barbituric acid

5-Bromo-5-phenyl-barbituric acid (7 mmol) andN-(methyl-p-tolyl)piperazin (8 mmol) are suspended in 40 ml absoluteethanol. After 2 hours under reflux it is concentrated in a vacuum. Theresidue is triturated with diethyl ether, sucked off, rewashed with 20ml diethyl ether and dried. The crude product is purified bychromatography on silica gel (acetone). One obtains colouriess crystals.Yield 72%; Fp. 247-48° C.

EXAMPLE 35-(1-[4-(4-(4-Methylphenyl))butyl]piperzinyl]-5-phenyl-barbituric acid

4-(p-Tolyl)-butyl bromide

The compound is prepared analogously to the literature. Synth. Commun.22(20)2945-8 (1992). Yield 91% colourless oil.

Phenyl-(4-(p-tolyl)-butyl)-malonic acid diethyl ester

Phenylmalonic acid diethyl ester (8.8 mmol) dissolved in 5 ml absolutetetrahydrofuran is added dropwise to 20 ml absolute tetrahydrofuran andsodium hydride (9.7 mmol). Then 4-p-tolylbutyl bromide (8.8 mmol)dissolved in 10 ml absolute tetrahydrofuran is added after 15 minutes.It is heated for 3 days under reflux. The solvent is concentrated in avacuum. The residue is taken up in 50 ml acette and extracted with 2×50ml water. The organic phase is dried over magnesium sulfate, filteredand concentrated by evaporation. It is purified by chromatography onsilica gel (heptane/ethyl acetate 9:1). Yield 55% colouriess oil.

5-1-[4-(4-(4methylphenyl))butyl]piperazinyl)-5-phenyl-barbituric acid

Urea (4.6 mmol) and phenyl4-(p-tolyl)-butyl)-malonic acid diethyl ester(3.1 mmol) are added to a solution of sodium ethylate (6.2 mmol) inabsolute ethanol. It is heated for 12 hours under reflux, thenconcentrated in a vacuum and the residue is taken up in 15 ml water. Themixture is adjusted to pH 1-2 with 6 N hydrochloric acid and extractedwith 2×30 ml ethyl acetate. The organic phase is dried over magnesiumsulfate, filtered and concentrated by evaporation. The residue ispurified by chromatography on silica gel (heptane/ethyl acetate 3:1).Yield 46% colourless crystals; Fp. 163-5° C.

EXAMPLE 4 5-(1-[4-(2-Hydroxyethyl)piperidinyl])-5-phenyl-barbituric acid

14.6 g (50 mmol) phenylmalonic acid diethyl ester and subsequently 10 g(166 mmol) urea are slowly added to 1.3 g sodium in 40 ml methanol whilestirring. It is heated for 2 hours while slightly boiling. In thisprocess a precipitate forms. It is cooled to 10-15° C., subsequentlyslowly admixed with 12.9 g (100 mmol) 4-(2-hydroxyethyl)piperidine, 13.8g (100 mmol) potassium carbonate and 2.87 ml (112.3 mmol) bromine. Themixture is stirred for 2 hours at 10-15° C., then slowly heated toboiling and boiled for 1 hour under reflux. After cooling it is pouredonto 240 ml 1 n nitric acid, the solution is washed once with tolueneand neutralized with a saturated sodium acetate solution. A greasy massprecipitates which is taken up in hot ethanol. The hot solution istreated with active carbon and admixed with warm water until turbiditystarts. After cooling the crystals are suction filtered. Yield: 7.3g=44%; Fp.: 222-223° C.

EXAMPLE 5 5-Phenyl-5-(1-piperidinyl)barbituric acid

5-Phenyl-5-(1-piperidinyl)barbituric acid in a yield of 92%; Fp.:244-246° C. is obtained analogously to example 4 using piperidineinstead of 4-(2-hydroxyethyl) piperidine.

EXAMPLE 6 5-[1-(4-Hydroxy)piperidinyl]-5-phenyl-barbituric acid

5-[1-(4-Hydroxy)piperidinyl]-5-phenyl-barbituric acid in a yield of 39%;Fp.: 241-242° C. (from ethanol) is obtained analogously to example 4using 4-hydroxy-piperidine instead of 4-(2-hydroxyethyl)piperidine.

EXAMPLE 7 5-[1-(4,4-Dimethyl)piperidinyl]-5-phenyl-barbituric acid

5-[1-(4,4-Dimethyl)piperidinyl]-5-phenyl-barbituric acid in a yield of69%; Fp.: 238-240° C. (from ethanol/water) is obtained analogously toexample 4 using 4,4-dimethylpiperidine instead of4-(2-hydroxyethyl)piperidine.

EXAMPLE 8 5-[1-(4-Methyl)-piperidinyl]-5-phenyl-barbituric acid

5-[1-(4-Methyl)piperidinyl]-5-phenyl-barbituric acid in a yield of 87%;Fp.: 208-209° C. (from methanol/water) is obtained analogously toexample 4 using 4-methyl-piperidine instead of4-(2-hydroxyethyl)piperidine.

EXAMPLE 9 5-[1-(4-Methoxy piperidinyl]-5-phenyl-barbituric acid

5-[1-(4-Methoxy)piperidinyl]-5-phenyl-barbituric acid in a yield of 67%;Fp.: 184-185° C. (from ethanol/water) is obtained analogously to example4 using 4-methoxy-piperidine instead of 4-(2-hydroxyethyl) piperidine.

EXAMPLE 10 5-Ethyl-5-[1-(4-methyl)piperidinyl]barbituric acid

14.1 g (75 mmol) ethylmalonic acid diethyl ester and subsequently 15 g.(264 mmol) urea is slowly added to 1.95 g sodium in 60 ml methanol whilestirring. After boiling for 2 hours a precipitate forms. It is cooled to10-15° C. and successively slowly admixed with 15 g (15 mmol)4-methylpiperidine. 21 g (150 mmol) potassium carbonate and 4.3 ml (168mmol) bromine. The mixture is stirred for 2 hours at this temperature,slowly heated to boiling and heated for 1 hour under reflux. Aftercooling it is poured onto 360 ml 1 N nitric acid, the solution is washedonce with toluene and admixed with an excess of saturated sodium acetatesolution. The precipitated precipitate is recrystallized from ethanolwith addition of active carbon. Yield: 4.4 g=23%; Fp.: 194-195° C.

EXAMPLE 11 5-Ethyl-5-[1-(4-methoxy)piperidinyl]barbituric acid

5-Ethyl-5-[1-(4-methoxy)piperidinyl]barbituric acid in a yield of 15%;Fp.: 201-202° C. (from ethanol) is obtained analogously to example 10using 4-methoxypiperidine instead of 4-methylpiperidine.

EXAMPLE 12 5-Ethyl-5-(1-(4-hydroxy)piperidinyl]barbituric acid

5-Ethyl-5-[1-(4-hydroxy)piperidinyl]barbituric acid in a yield of 5%;Fp.: 110-112° C. (from ethanol) is obtained analogously to example 10when using 4-hydroxypiperidine instead of 4-methoxypiperidine.

EXAMPLE 13 5-Ethyl-5-[1-(4-(2-hydroxyethyl)piperidinyl)]barbituric acid

5-Ethyl-5-[1-(4-(2-hydroxyethyl)piperidinyl)]barbituric acid in a yieldof 17%; Fp.: 238-240° C. (from methanol) is obtained analogously toexample 10 using 4-(2-hydroxyethyl)piperidine instead of4-methylpiperidine.

EXAMPLE 145-(4-methoxyphenyl-5-[N-(2-hydroxyethyl)pipierazinyl]barbituric acid

a) Preparation of Ethyl 4-methoxyphenylacetate

A solution of 4-methoxyphenylacetic acid (2 g) and para-toluensulfonicacid (230 mg) in 30 ml of ethanol is refluxed for 2 hours. The solventis evaporated under reduced pressure and the residue is suspended in asaturated aqueous solution of sodium hydrogencarbonate and extractedtwice with ethyl acetate. The organic extracts are collected, washedwith water and dried over sodium sulfate to give, after evaporation ofthe solvent under reduced pressure, 2.14 g of the product.

b) Preparation of Ethyl 4-methoxyphenyl Malonate

A mixture of ethyl 4-methoxyphenylacetate (27.8 g) and sodium (3.68 g)in 90 ml of diethylcarbonate is refluxed for 3 hours, then the solventis evaporated under reduced pressure and the residue is diluted withwater and neutralized with acetic acid. The aqueous phase is extractedtwice with diethyl ether. The organic extracts are pooled and washedtwice with 1 N sodium hydroxide and once with water, then the organicphase is dried over sodium sulfate and concentrated to dryness. 34.2 gof the product are obtained.

c) Preparation of 5-(4-methoxyphenyl)barbituric acid

To a solution of 660 mg of sodium in 50 ml of ethanol are added 3.86 gof ethyl 4-methoxyphenyl malonate and 1.28 g of urea The reactionmixture is refluxed for 3 hours. A white solid separates, which iscollected by filtration and redissolved in 15 ml of water. The solutionis acidified to pH=1-2 by adding 6 N hydrochloric acid. A white solidseparates, which is filtered and washed on the filter with water. Afterdrying under vacuum at 50° C. for several hours, 2.28 g of the productare obtained.

d) Preparation of 5-bromo-5-(4-methoxyphenyl)barbituric acid

To a suspension of 5-(4-methoxyphenyl)barbituric acid (222 mg) in 3 mlof water, cooled to 0-5° C. with ice bath, are added 136 μl of 48%hydrobromic acid and 56 μl of bromine, dropwise. After 1 hour at atemperature below 10° C., the solid which separated is collected byfiltration and washed on the filter with water. The solid is dried forseveral hours under vacuum at 50° C., to give 283 mg of the product.

e) Preparation of the Title Compound

A solution of 5-bromo-5-(4-methoxyphenyl)barbituric acid (11.5 g) andN-(2-hydroxyethyl) piperazine (15.755 g) in 260 ml of methanol isrefluxed for about 2 hours, then the solid which separated is collectedby filtration, redissolved in 100 mnl of methanol and heated at refluxfor 1 hour. The solid is filtered again and dried at 80° C. under vacuumto give 9 g of the product containing 8-9% of methanol. The solid isdissolved in 40 ml of 1 N hydrochloric acid, then the solution isbasified with 3.42 g of sodium hydrogencarbonate and cooled at 0-5° C.for 4 hours. The product is recovered by filtration and it is driedunder vacuum at 80° C. for several hours, to give 8.55 g of the pureproduct, m.p. 247-248° C.

¹ H-NMR in d6-DMSO: 2.36 ppm (m, 6H); 2.55 ppm (m, 4H); 3.44 ppm (q,2H); 3.74 ppm (s, 3H); 4.33 ppm (t, 1H); 6.95 ppm (d, 2H); 7.3 ppm (d,2H); 11.54 ppm (br s, 2H).

EXAMPLE 155-[3-(4-methoxyphenyl)propyl]-5-[4-(2-hydroxyethyl)piperazinyl]barbituric acid

a) Preparation of 3-(4-methoxyphenyl)propionyl Chloride

To a suspension of 3-(4-methoxyphenyl)propionic acid (10 g) in 150 ml oftoluene are added 8 ml of thionyl chloride and the mixture is heated to65° C. for 4 hours. The solvent is evaporated off under reduced pressureand the residue is redissolved in toluene and concentrated to dryness.Such steo is repeated twice. 11 g of the product are obtained as ayellow oil.

b) Preparation of 5-[3-(4-methoxyphenyl)propionyl]barbituric acid

To a suspension of barbitunric acid (6.4 g) in 48 ml of pyridine areadded dropwise 11 g of 3-(4-methoxyphenyl)propionyl chloride and themixture is stirred at room temperature for 18 hours. The reactionmixture is then poured into ice and acidified to pH=1 by adding 6 Nhydrochloric acid. A solid precipitates, which is filtered andresuspended in methanol. The suspension is kept under stirring for 15minutes, then the solid is recovered by filtration to give 12.2 g of theproduct. m.p. 248-250° C.

c) Preparation of 5-[3-(4-methoxyphenyl)propyl]barbituric acid

To a suspension of 10 g of 5-[3-(4-methoxyphenyl)propionyl]barbituricacid in 100 ml of acetic acid are added portionwise 4.5 g of sodiumcyanoborohydride, then the mixture is heated to 600° C. After 1 hour thereaction mixture is cooled to room temperature and poured into ice.After 30 minutes a solid is recovered by filtration, which is driedunder vacuum at 50° C. to give 8.74 g of the product, m.p. 195-197° C.

d) Preparation of 5-bromo-5-[3-(4-methoxyphenyl)propyl]barbituric acid

A mixture of 5-[3-(4-methoxyphenyl)propyl]barbituric acid (2.5 g),N-bromosuccinimide (2 g) and dibenzoyl peroxide (catalytic amount) in110 ml of carbon tetrachloride is refluxed for about 1 hour then thesolid which separated is filtered. The solid is redissolved in ethylacetate and filtered through a silica gel cake in order to eliminate thesuccinimide residue. The organic phase is then concentrated to drynessand the residue is crystallized from diethylether/carbon tetrachloridemixture. A pale yellow solid separates which is filtered and dried undervacuum at 60° C. to give 2.8 g of the product. m.p. 113-114° C.

e) Preparation of the Title Compound

A mixture of 5-bromo-5-[3-4-methoxyphenyl)propyl]barbituric acid (710mg) and N-(2-hydroxyethyl)piperazine (281 mg) in 25 ml of ethanol isrefluxed for 4 hours. The solvent is evaporated under reduced pressureand the residue is partitioned between 1 N hydrochloric acid and ethylacetate. The aqueous phase is basified to pH=6-7 and extracted withethyl acetate. The organic phase is concentrated to dryness and theresidue is crystallized from ethyl acetate to give 30 mg of the product.

¹ H-NRM in d6-DMSO: 1.32 ppm (m, 2H1); 1.86 ppm (m, 2H); 2.33 ppm (m,6H); 2.45 ppm (m, 2H); 2.53 ppm (m, 4H); 3.43 ppm (q, 2H); 3.7 ppm (s,3H); 4.35 ppm (t, 1H); 6.8 ppm (d, 2H); 7.04 ppm (d, 2H); 11.53 ppm (brs, 2H).

EXAMPLE 16 5-phenyl-5-[4-(2-hydroxyethylidene)piperidinyl]barbituricacid

a) Preparation of 4-(ethoxycarbonylmethylidene)piperidine

To a suspension of sodium hydride (2.6 g) in 30 ml of tetrahydrofuran,cooled to 0° C. and kept under nitrogen atmosphere, 13 ml oftriethylphosphonoacetate, dissolved in 10 ml of tetahydrofuran, areadded dropwise. The temperature is then brought to room temperature andthe stirring is continued for 30 minutes. The mixture is again cooled to0° C. and it is added dropwise with a solution obtained by addingportionwise to a solution of 4-piperidone monohydrate hydrochloride (10g) in THF 2.6 g of sodium hydride filtered to eliminate the sodiumchloride which formed. At the end of the addition, the temperature isbrought to room temperature and the stirring is continued for 20 hours.The solvent is then evaporated under reduced pressure and the residue isredissolved in ethyl acetate and washed with 1 N hydrochloric acid. Theaqueous phase is extracted with ethyl acetate and chloroform, then it isbasified to pH=9-10 by adding 20% sodium hydroxide and it is extractedwith chloroform. The aqueous phase is then salted and extracted againwith chloroform three times. The pooled extracts are dried over sodiumsulfate and evaporated to give 7.1 g of the product as a yellow oil.

b) Preparation of 4-(hydroxyethylidene)piperidine

A solution of 15 ml of DIBAL (1.5 M solution in toluene) in 20 ml oftoluene is added dropwise with 0.976 g of4-(ethoxycarbonylmethylidene)piperidine, dissolved in few milliliter oftoluene. The reaction mixture is stirred at room temperature for 2hours, then it is cooled to 0-5° C. and added dropwise with methanol,until the gaz development is seen. The mixture is concentrated to alittle volume and diethyl ether is added: a white solid separates, whichis filtered off. The organic phase is concentrated to dryness,redissolved in diethyl ether and again filtered. The clear solution isconcentrated to dryness to give 500 mg of the product.

c) Preparation of the Title Compound

A mixture of 5-bromo-5-phenylbarbituric acid (2.45 g),4-(hydroxyethylidene)piperidine (1.053 g) and triethylamine (1.15 ml) in50 ml of ethanol is refluxed for 2 hours. The solvent is evaporatedunder reduced pressure and the residue is purified by silica gelchromatography (40 g; eluent: ethyl acetate/petroleum ether 8:2), togive 450 mg of the product.

¹ H-NMR in d6-DMSO: 2.13 ppm (m, 4H); 2.55 ppm (m, 4H); 3.89 ppm (d,2H); 4.46 ppm (br s, 1H); 5.24 ppm (t, 1H); 7.42 ppm (m, 5H); 11.6 ppm(br s, 2H).

50 mg of5-phenyl-5-[4-(2-hydroxyethyl)-1,2,5,6-tetrahydropyridinyl]barbituricacid as a side product are also recovered.

¹ H-NMR in d6-DMSO: 1.96 ppm (m, 2H); 2.09 ppm (t, 2H); 2.64 ppm (t,2H), 3.00 ppm (m, 2H); 3.47 ppm (q, 2H); 4.43 ppm (t, 1H); 5.3 ppm (m,1H); 7.4 ppm (s, 5H); 11.63 ppm (br s. 2H).

EXAMPLE 17 5-phenyl-5-[N-(2-hydroxyethyl)piperazinyl]-2-thiobarbituricacid

a) Preparation of Diethyl 2-bromo-2-phenylmalonate

To a solution of diethyl 2-phenylmalonate (15 ml) in 200 ml oftetrahydrofuran, kept at 0° C. and under nitrogen atmosphere, 3.475 g ofsodium hydride are added and the mixture is kept 30 minutes understirring at 0° C., then it is brought to room temperature.

After cooling again to 0° C., the reaction mixture is added with 14.3 gof N-bromosuccinimide. After about 15 minutes, the white solid whichseparated is filtered off and the filtrate is concentrated to dryness togive a residue which is redissolved in chloroform and dried over sodiumsulfate. The solvent is evaporated under reduced pressure to give 15.66g of the product.

b) Preparation of Diethyl2-phenyl-2-[4-(2-hydroxyethyl)piperazinyl]malonate

A solution of diethyl 2-bromo-2-phenylmalonate (16.8 g) in 150 ml ofdimethylsulfoxide is heated to 90-100° C., thenN-(2-hydroxyethyl)piperazine (27.9 g) is added and the reaction mixtureis heated for additional 4 hours. The mixture is poured into water andextracted with ethyl acetate three times. The pooled organic extractsare washed with 1 N hydrochloric acid. The aqueous phase is basifiedwith 1 N sodium hydroxide to pH=8-9 and it is extracted twice with ethylacetate. The organic extracts are collected and are washed with asaturated aqueous solution of sodium chloride and dried over sodiumsulfate. After removal of the solvent under reduced pressure, theresidue is crystallized from diethylether petroleum ether 1:1 to give6.5 g of the product, m.p. 63-64° C.

c) Preparation of the Title Compound

To a solution of sodium (27 mg) in 3 ml of ethanol are added 218 mg ofdiethyl 2-phenyl-2-[4-(2-hydroxyethyl)piperazinyl]malonate and 288 mg ofthiourea, then the mixture is refluxed for about 13 hours. The reactionmixture is cooled to room temperature and 140 μl of acetic acid areadded, then the solvent is evaporated under reduced pressure. Theresidue is redissolved in a ethyl acetate/methanol 9:1 mitre. The solidwhich separates is filtered off and the filtrate is concentrated todryness and purified by silica gel chromatography (eluent: from ethylacetate to ethyl acetate/methanol 9:1), to give, after crystallizationfrom ethyl acetate, 30 mg of the product, m.p. >250° C.

¹ H-NMR in d6-DMSO: 2.4 ppm (m, 6H); 2.59 ppm (m, 4H); 3.46 ppm (q, 2H);4.4 ppm (t, 1H); 7.4 ppm (m, 5H); 12.5 ppm (br s, 2H).

EXAMPLE 18 5-phenyl-5-[N-(2-hydroxyethyl)piperazinyl]-2-azobarbituricacid

To a solution of sodium (70 mg) in 5 ml of ethanol are added 218 mg ofdiethyl 2-phenyl-2-[4-2-hydroxyethyl)piperazinyl]maionate (example4-step b) and 172 mg guanidine hydrochloride and the mixture is refluxedfor 8 hours. Further 57 mg of guanidine hydrochloride are added and themixture is refluxed for additional 6 hours. The temperature is broughtto room temperature and acetic acid is added until neutralizationoccurs, then the solid which is formed is filtered off. The filtrate isconcentrated to dryness and redissolved in ethanol, from which by addingof ethyl acetate a solid separates. After 1 hour at -4° C. the whitesolid is recovered by filtration and it is recrystallized from methanol(2 ml), to give, after drying under vacuum at 90° C. for 4 hours. 78 mgof the product. m.p. >250° C.

¹ H-NMR in d6-DMSO: 2.33 ppm (m, 6H); 2.54 ppm (m, 4H); 3.41 ppm (t,2H); 4.33 ppm (br s, 1H); 7.00 ppm (br s, 1H); 7.33 ppm (m, 5H); 7.5 ppm(br s, 1H); 11.4 ppm (br s, 1 H).

EXAMPLE 19 5-benzyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid

a) Preparation of 5-benzylidenebarbituric

A suspension of 5 g of barbituric acid in 50 ml of water is heated untila compklete dissolution occurs, then it is added with 4.3 ml ofbenzaldheide. The mixture is refluxed for 1 hour, then the solid whichseparated is filtered, washed several times with water and dried undervacuum at 100° C., to give 8.17 g of the product, m.p. >258° C.

b) Preparation of 5-benzylbarbituric acid

To a suspension of 5-benzylidenebarbituric acid (4 g) in 200 ml ofmethanol are added portionwise 1.4 g of sodium borohydride. After 10minutes from the end of the addition, 100 ml of water are added and themixture is acidified with 1 N hydrochloric acid to pH=2. The solvent isevaporated off and the aqueous phase is extracted with ethyl acetate.The pooled extracts are dried over sodium sulfate and concentrated todryness. 3.6 g of the product crystallize, m.p. 207-209° C.

c) Preparation of 5-bromo-5-benzylbarbituric acid

To a suspension of 5-benzylbarbituric acid (1.7 g) in 15 ml of water,cooled to 0-5° C., 1 ml of 48% hydrobromic acid are added followed bythe addition dropwise of 0.437 ml of bromine into the reaction mixture.After 1 hour under stirring at a temperature below 10° C. the solidwhich formed is separated by filtration and washed with water. 2.17 g ofthe product are obtained. m.p. 164-166° C.

d) Preparation of the Title Compound

A solution of 5-bromo-5-benzylbarbituric acid (2.15 g) andN-(2-hydroxyethyl)piperazine in 50 ml of ethanol is refluxed for 4hours, then it is cooled to room temperature and added with 4 ml oftriethylamine. The solvent is evaporated off and the white residue isredissolved in a ethyl acetatemethanol 3:1 mixture. An orange solidcrystallizes, which is recovered by filtration. After recrystallizationfrom ethanol 0.62 g of the product are obtained, m.p. 243-246° C.

¹ H--NMR in d6-DMSO: 2.43 ppm (t, 2H); 2.58 ppm (m, 4H); 3.03 ppm (m,4H); 3.34 ppm (s, 2H); 3.49 ppm (q, 2H); 4.5 ppm (t, 1H); 7.13 ppm (m,5H); 8.8 ppm (br s, 2H).

EXAMPLE 205-[N-(2-hydroxyethyl)piperazinyl]-5-(4-hydroxyphenyl)barbituric acid

a) Preparation of 5-(4-hydroxyphenyl)barbituric acid

To a suspension of 5-(4-methoxyphenyl)barbituric acid (222 mg) in 5 mlof methylene chloride, kept at -5/-10° C. and under nitrogen atmosphere,is dropped a solution of boron tribromide (473 μl) in 2 ml of methylenechloride. The stirring is continued for additional 2 hours at -5° C.,then the temperature is brought to room temperature and stirring iscontinued for further 20 hours. The reaction mixture is again cooled to0° C. with an ice bath and it is basified to pH=9-10 by adding dropwise5% sodium hydroxide. The aqueous phase is separated, filtered through acelite plug, cooled with ice bath and acidified to pH=1 with 37%hydrochloric acid. A white solid separates which after 1 hour isseparated by filtration and dried under vacuum at 60° C. to give 215 mgof the product.

b) Preparation of 5-[4-(tertbutyldimethylsilyloxy)phenyl]barbituric acid

To a solution of 5-(4-hydroxyphenyl)barbituric acid (1.9 g) andtertbutyl dimethylsilyl chloride (4.68 g) in 20 ml of anhydrousdimethylformlamde are added 4.4 g of imidazole and the mixture is heatedto 55° C. for 5 hours. The temperature is then brought to roomtemperature and the reaction mixture is poured into 1 N hydrochloricacid and extracted twice with ethyl acetate. The pooled organic extractsare washed with water and dried over sodium sulfate. By concentration ofthe solution a white solid separates, which is kept at 0° C. overnight,then it is filtered to give 2.185 g of the product

c) Preparation of5-bromo-5-[(4-tertbutyldimethylsilyloxy)phenyl]barbituric acid

To a suspension of 5-[4-(tertbutyldimethylsilyloxy)phenyl]barbituricacid (330 mg) and dibenzoyl peroxide (catalytic amount) in 10 ml ofcarbon tetrachloride are added 210 mg of N-bromosuccinimide. The mixtureis stirred at room temperature for 1 hour, then the solvent isevaporated off and the residue is purified by silica gel chromatography(eluent: petroleum ether/ethyl acetate 8:2), to give 260 mg of theproduct.

d) Preparation of5-[N-(2-hydroxyethyl)piperazinyl]-5-[(4-tertbutyldimethylsilyloxy)phenyl]barbituricacid

A solution of 5-bromo-5-[(4-tertbutyldimethylsilyloxy)phenyl]barbituricacid (260 mg) and N-(2-hydroxyethyl)piperazine (98 mg) in 5 ml ofethanol is refluxed for 1 hour, then it is brought to room temperatureand added with 0.3 ml of triethylamine. The solvent is evaporated offand the residue is purified by silica gel chromatography (25 g; eluent:ethyl acetate/methanol 3:1), to give, after crystallization from ethylacetate, 170 mg of the product, m.p. 220-221° C.

e) Preparation of the Title Compound

A mixture of5-[N-(2-hydroxyethyl)piperazinyl]-5-[(4-tertbutyldimethylsilylfoxy)phenyl]barbituricacid (148 mg), tetrabutylammonium fluoride (1.1 M in THF; 0.6 ml) andacetic acid (290 μl) in 10 ml of tetrahydrofuran, kept at 0° C., isstirred for 2 hours 30 minutes, then the solvent is evaporated off andthe residue is purified by silica gel chromatography (12 g; eluent:ethyl acetatelmethanol 3:1), to give, after crystallization from ethylacetate and recrystallizalion from ethyl acetate/methanol mixture. 40 mgof the product, m.p. >25° C.

¹ H-NMR in d6-DMSO: 2.37 ppm (m, 6H); 2.55 ppm (m, 4H); 3.45 ppm (q,2H); 4.35 ppm (t, 1H); 6.76 ppm (d, 2H); 7.17 ppm (d, 2H); 9.72 ppm (s,1H); 11.47 ppm (br s, 2H).

EXAMPLE 215-[N-(2-hydroxyethyl)piperazinyl]-5-(3-hydroxyphenyl)barbituric acid

a) Preparation of Ethyl 3-hydroxyphenylacetate

A suspension of 3-hydroxyphenylacetic acid (5.4 g) andpara-toluensulfonic acid (650 mg) in 80 ml of ethanol is refluxed for 4hours, then the solvent is evaporated off and the residue is dissolvedin ethyl acetate and washed twice with a saturated aqueous solution ofsodium hydrogencarbonate. The organic phase is dried over sodium sulfateand the solvent is evaporated off to give 6.08 g of the product as ayellow oil.

b) Preparation of Ethyl 3-(tertbutyldimethylsilyloxy)phenylacetate

To a solution of ethyl 3-hydroxyphenylacetate (6 g) andtertbutyldimethylsilyl chloride (6 g) in 80 ml of anhydrousdimethylformamide are added 5.66 g of imidazole and the mixture isstirred at room temperature for 1 hour 30 minutes. The reaction mixtureis then poured into water and extracted twice with ethyl acetate. Thepooled organic extracts are dried over sodium sulfate and concentratedto dryness to give 10 g of the product as a yellow oil.

c) Preparation of Diethyl 3-(tertbutyldimethylsilyloxy)phenylmalonate

To a solution of ethyl 3-(tertbutyldimethylsilyloxy)phenylacetate (10 g)in 25 ml of diethylcarbonate are added portionwise 0.86 g of sodium andthe mixture is refluxed for 2 hours. The solvent is evaporated off andthe residue is poured into water (90 ml). The pH is adjusted to pH=6with acetic acid and the mixture is extracted with diethyl ether. Theorganic phase is dried over sodium sulfate and cocentrated to dryness togive 10 g of an orange oil which is purified by silica gelchromatography (eluent: petroleum ether/ethyl acetate 95:5), to give2.45 of the product.

d) Preparation of 5-[3-(tertbutyldimethylsilyloxy)phenyl]barbituric acid

To a solution of diethyl 3-(tertbutyldimethylsilyloxy)phenylmalonate(1.5 g) in 15 ml of ethanol are added 0.445 g of sodium ethoxide and0.295 g of urea and the mixture is refluxed for 3 hours. The reactionmixture is cooled to room temperature and the solid formed is filtered.The solid is redissolved in water, the pH is adjusted to pH=1-2 with 6 Nhydrochloric acid and the soild which precipitates is recovered byfiltration. The filtrate is concentrated to eliminate the ethanol, thenthe solution is basified and extracted with ethyl acetate. The organicphase is concentrated to dryness to give 250 mg of residue which ispooled with the solid previously filtered (350 mg). The residue soobtained contains a mixture of the product along with the de-silylatedderivative.

Such a residue (550 mg) is dissolved in 5 ml of anhydrousdimethylformamide and 790 mg of tertbutyldimethylsilyl chloride and 745mg of imidazole are successively added.

The mixture is heated to 55° C. for 5 hours. Furher 75 mg of imidazoleand 79 mg of tenbutyldimethylsilyl chloride are added and the heating iscontinued for an additional hour. The reaction mixture is then pouredinto 1 N hydrochloric acid and extracted three times with ethyl acetate.The pooled organic extracts are washed with water and dried over sodiumsulfate. The solution is concentrated and a white solid precipitates.710 mg of the product are recovered by filtration.

e) Preparation of5-[3-(tertbutyldimethylsilyloxy)phenyl]-5-bromobarbituric acid

A mixture of 5-[3-(tertbutylidimethylsilyloxy)phenyl]barbituric acid(680 mg), N-bromosuccinimide (432 mg) and dibenzoyl peroxide (catalyticamount) in 10 ml of carbon tetrachloride are stirred at room temperaturefor 1 hour. The solvent is evaporated off and the residue is purified bysilica gel chromatography (eluent: ethyl acetate/hexane 7:3) to give 550mg of the product, m.p. 170-172° C.

f) Preparation of5[-N-(2-hydroxyethyl)piperazinyl]-5-[3-(tertbutyldimethylsilyloxy)phenyl]barbituricacid

A solution of 5-[3-(tertbutyldimethylsilyloxy)phenyl]-5-bromobarbituricacid (444 mg) and N-(2-hydroxyethyl)piperazine (420 mg) in 10 ml ofmethanol is stirred at room temperature for 5 hours, then the solvent isevaporated off and the residue is purified by silica gel chromatography(13 g; eluent: ethyl acetate/methanol 3:1), to give 70 mg of theproduct.

g) Preparation of the Title Compound

To a solution of5-[N-(2-hydroxyethyl)piperazinyl]-5-[3-(tertbutyldimethylsilyloxy)phenyl]barbituricacid (170 mg) in 12 ml of tetrahydrofuran, kept at 0° C. and undernitrogen atmosphere, are added 333 μl of acetic acid and 0.69 ml oftetrabutylammonium fluoride. The mixture is stirred for 3 hours then thesolvent is evaporated off and the residue is purified by silica gelchromatography (15 g; eluent: ethyl acetate/methanol 4:1), to give,after crystallization from methanol, 35 mg of the product, m.p. 219-221°C.

¹ H-NMR in d6-DMSO: 2.37 ppm (m, 6H);, 2.59 ppm (m, 4H); 3.45 ppm (q,2H); 4.35 ppm (t, 1H); 6.74 ppm (m, 2H); 6.92 ppm (t, 1H); 7.18 ppm (t,1H); 9.62 ppm (s, 1H); 11.54 ppm (br s, 2H).

EXAMPLE 225-[N-(2-hydroxyethyl)piperazinyl]-5-(4-methylphenyl)barbituric acid

a) Preparation of 5-(4-methylphenyl)barbituric acid

To a solution of sodium (184 mg) in 12 ml of ethanol are added 0.95 mlof diethyl 2-(4-methylphenyl)malonate and 360 mg of urea, then themixture is refluxed for 3 hours. A white solid separates, which isfiltered and redissolved in 4 ml of water. The solution is acidified topH=1-2 by adding 6 N hydrochloric acid, A white solid separates, whichis collected by filtration, washed with 15 ml of water and dried undervacuum. 619 mg of the product are obtained. m.p. 271° C.

b) Preparation of 5-bromo-5-(4-methylphenyl)barbituric acid

To a suspension of 5-(4-methylphenyl)barbituric acid (218 mg) in 2 ml ofwater, kept at 10° C. under stirring, 136 μl of 48% hydrobromic acid areadded, then 56 μl of brominr are dropped and the stirring is continuedfor 3 hours. The precipitate which formed is recovered by filtration andwashed with water. then it is dried under vacuum to give 270 mg of theproduct, m.p. 210-213° C.

c) Preparation of the Title Compound

A solution of 5-bromo-5-(4-methylphenyl)barbituric acid (3.1 g) and ofN-(2-hydroxyethyl) piperazine (1.53 g) in 60 ml of ethanol is refluxedfor 3 hours. The solvent is evaporated off and the residue is dissolvedin 1 N hydrochloric acid and washed twice with ethyl acetate. Theaqueous phase is basified with 1 N sodium hydroxide and extracted withethyl acetate. The organic extracts are concentrated to dryness and theresidue is purified by silica gel chromatography (100 g; eluent: ethylacetate/methanol 3:1), to give, after evaporation of the solvent, 1.97 gof the product as hydrobromide.

The free base is obtained by treating an ethyl acetate suspension (200ml) of the salt with 50 ml of a saturated aqueous solution of sodiumhydrogencarbonate and by extraction of the aqueous phase with ethylacetate. By concentrating to dryness the pooled organic extracts 1.18 gof the product are obtained.

¹ H-NMR in d6-DMSO: 2.3 ppm (s, 3H); 2.35 ppm (m, 6H); 2.57 ppm (m, 4H);3.45 ppm (q, 2H); 4.35 ppm (t, 1H); 7.19 ppm (d, 2H); 7.28 ppm (d, 2H);11.55 ppm (br s, 2H).

EXAMPLE 23 5-octyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid

a) Preparation of Diethyl 2-octylmalonate

To a solution of 2.63 of sodium in 100 ml of ethanol is added dropwise asolution of 19.1 ml of diethylmalonate in 10 ml of ethanol. The mixtureis successively added with 20.4 ml of 1-bromooctane dissolved in 10 mlof ethanol, then the mixture is refluxed for 6 hours. The reactionmixture is concentrated to a little volume and the residue ispartitioned between a saturated aqueous solution of sodiumhydrogenphosphate (200 ml) and ethyl acetate (200 ml). The organic phaseis washed with 75 ml of water and 75 ml of saturated aqueous solution ofsodium chloride, dried over sodium sulfate and concentrated to dryness.to give 31.8 g of the product as an oil.

¹ H-NMR in CDCl₃ ; 0.80-0.95 ppm (m, 3H); 1.15-1.40 ppm (m, 18H); 1.88ppm (q, 2H); 3.33 ppm (t, 1H); 4.19 ppm (q, 4H).

b) Preparation of 5-octylbarbituric acid

To a solution of sodium (5.32 g) in 400 ml of anhydrous ethanol is addeda solution of diethyl 2-octylmalonate (31.5 g) in 50 ml of ethanol andsuccessively 10.27 g of urea, then the mixture is refluxed for 2 hours30 minutes. The mixture is rapidly cooled to room temperature and thesolid which was formed is recovered by filtration and washed withdiethyl ether. The solid is then dissolved in 200 ml. of water andacidified with 6 N hydrochloric acid until pH 1.5-2 is reached. A solidseparates. The mixture is added with 200 ml of ethyl acetate and it isstirred for 2 hours, then it is added with additional 800 ml of warmethyl acetate. The organic phase is separated and the aqueous phase iswashed with 200 ml of ethyl acetate. The pooled organic phases arewashed with 250 ml of saturated aqueous solution of sodium chloride,dried over sodium sulfate and concentrated to dryness. 21.03 g of theproduct are obtained.

¹ H-NMR in d6-DMSO: 0.77-0.80 ppm (m, 3H); 1.23 ppm (s, 12H); 1.80-1.95ppm (m, 2H); 3.52 ppm (t, 1H); 11.15 ppm (s, 2H).

c) Preparation of 5-bromo-5-octylbarbituric acid

To a suspension of 5-octylbarbituric acid (20 g) in 120 ml of water,cooled at 0-5° C., are added 12 ml of 48% hydrobromic acid andsuccessively are dropped 4.72 ml of brornine. After 2 hours understirring, the white solid which separated is recovered by filtration,washed with water and partitioned between 200 ml of diethyl ether and100 ml of water.

The aqueous phase is extracted with additional 50 ml of diethyl ether.The pooled 25 organic phases are washed with 75 ml of saturated aqueoussolution of sodium chloride, dried over sodium sulfate and concentratedto dryness. 25.8 g of the product as white solid are obtained.

¹ H-NMR in d6-DMSO: 0.78-0.90 ppm (m, 3H); 1.10-1.38 ppm (m, 12H);2.20-2.34 ppm (m, 2H); 11.80 ppm (s, 2H).

d) Preparation of the Title Compound

To a solution of 5-bromo-5-octylbarbituric acid (23.52 g) in 70 ml ofdimethylsulfoxide, kept under nitrogen atmosphere and at a temperatureof 5-10° C., is dropped N-(2-hydroxyethyl)piperazine (36.2 ml), then themixture is stirred at room temperature for 2 hours 30 minutes. Thereaction mixture is poured into water (1 l) under stirring and coolingwith an ice bath. The white solid which separates is recovered byfiltration washed with water and dried under vacuum at 40° C., to give,after crystallization from ethanol (140 ml) 10.91 g of the product as awhite solid, m.p. 183-184° C.

¹ H-NMR in d6-DMSO: 0.75-0.88 ppm (m, 3H); 0.90-1.10 ppm (m, 2H);1.12-1.30 ppm (m, 10H); 1.75-1.90 ppm (m, 2H); 2.23-2.40 ppm (m, 6H);2.45-2.60 ppm (m, 4H); 3.45 ppm (br t, 2H); 4.35 ppm (br s, 1H); 11.55ppm (s, 2H).

EXAMPLE 24 5-naphtyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid

a) Preparation of Ethyl 2-naphtylacetate

To a solution of 2-naphtylacetic acid (5 g) in 50 ml of ethanol areadded 0.5 g of para-toluensulfonic acid, then the reaction mixture isrefluxed for about 4 hours. The solvent is evaporated off and theresidue is dissolved in diethyl ether, washed twice with a saturatedaqueous solution of sodium hydrogencarbonate and once with brine, thenthe pooled organic extracts are dried over sodium sulfate andconcentrated to dryness. 5.64 g of the product as a yellow oil areobtained.

b) Preparation of Diethyl 2-naphtylmalonate

To a solution of ethyl 2-naphtylacetate (2 g) in 23.3 ml ofdiethylcarbonate, kept under stirring and at room temperature, are addedportionwise 0.232 g of sodium. The reaction mixture is refluxed for 2hours 30 minutes, then it is concentrated in order to eliminate the notreacted diethylcarbonate and it is added with 20 ml of cold water. Theresulting mixture is acidified with acetic acid until weak acidity isreached, then it is extracted three times with diethyl ether. The pooledorganic extracts are dried over sodium sulfate and the solvent isevaporated off, to give, after recrystallization from diethyl ether (19ml), 1.015 g of the product as a white solid.

c) Preparation of 5-naphtylbarbituric acid

A solution of sodium (0.32 g) in 30 ml of anhydrous ethanol is addedwith diethyl 2-naphtylmalonate (2 g) and successively with urea (0.63g). The mixture is refluxed for 2 hours, then the solid which separatedis recovered by filtration, then it is dissolved in 7 ml of water andacidified to pH=1 with 6 N hydrochloric acid. A white solid precipitateswhich, after 30 minutes under stirring, is filtered and washed withwater. The solid is dried overnight under vacuum at 40° C., to give 0.96g of the product.

d) Preparation of 5-bromo-5-naphtylbarbituric acid

A suspension of 5-naphtylbarbituric acid (0.2 g) in 1.5 ml of 95%ethanol, cooled at 0° C. and kept under stirring, is added dropwise with48% hydrobromic acid (0.5 ml) and successively with 4.4 μl of bromine.After 4 hours under stirring at room temperature the solid is filteredand washed with water, then it is dried under vacuum at 40° C.overnight. 0.25 g of the product are obtained.

e) Preparation of the Title Compound

To a suspension of 5-bromo-5-naphtylbarbituric acid (0.24 g) in 3.5 mlof ethanol is added a solution of N-(2-hydroxyethyl)piperazione (0.112g) in 1.5 ml of ethanol. The reaction mixture is refluxed for 5 hours,then it is cooled to room temperature and the solid which separates isfiltered off. The filtrate is added with 100 μl of triethylamine, thenthe solvent is evaporated off to give 0.364 g of a solid, which isrecrystallized from a mixture of methanol (4.5 ml) and ethyl acetate (10ml). The obtained solid (70 mg) is washed under stirring with an ethylacetate/water mixture for 2 hours and dried under vacuum at 40° C. for 8hours, to give 60 mg of the product.

¹ H-NMR in d6-DMSO: 2.3-2.5 ppm (m, 6H); 2.6 ppm (m, 4H); 3.45 ppm (m,2H); 4.35 ppm (t, 1H); 7.4-8.1 ppm (m, 7H); 11.65 ppm (s, 2H).

EXAMPLE 25 5-(4'-biphenyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituricacid

a) Preparation of Ethyl (4'-biphenyl)acetate

A suspension of (4'-biphenyl)acetic acid (6.4 g) in 60 ml of ethanol isadded with 1.1 g of para-toluensulfonic acid, then the reaction mixtureis refluxed for 4 hours 30 minutes. The solvent is evaporated off, theresidue is dissolved in diethyl ether and the resulting organic phase iswashed three times with a saturated aqueous solution of sodiumhydrogencarbonate and once with brine. The organic phase is then driedover sodium sulfate and the solvent is evaporated off to give 7.1 g ofthe product as a yellow oil.

b) Preparation of Diethyl (4'-biphenyl)malonate

A solution of ethyl (4'-biphenyl)acetate (7.1 g) in 60 ml ofdiethylcarbonate, kept under nitrogen atmosphere, is added portionwisewith sodium (0.734 g), then it is heated at 120° C. for 3 hours. Thesolvent is evaporated off and the residue is dissolved in 65 ml of coldwater and acidified with acetic acid until pH=5-6 is reached. Theaqueous phase is then extracted three times with diethyl ether and thepooled organic extracts are dried over sodium sulfate and concentratedto dryness. The residue is purified by silica gel chromatography(eluent: petroleum ether/diethyl ether 9.4:0.6) to give 7.05 g of theproduct. m.p. 51-53° C.

c) Preparation of 5-(4'-biphenyl)barbituric acid

A solution of sodium (0. 322 g) in 40 ml of anhydrous ethanol is addedwith diethyl (4'-biphenyl)malonate (2.2 g) and successively with urea(0.63 g). The reaction mixture is refluxed for 3 hours 30 minutes, thenit is cooled to room temperature and the solid is recovered byfiltration. The obtained solid is redissolved in 40 ml of warm water andthe resulting aqueous phase is acidified to pH=1 with 6 N hydrochloricacid. The solid which separates is kept 15 minutes under stirring, thenit is filtered and dried under vacuum at 60° C. 1.1 g of the product areobtained, m.p. >240° C.

d) Preparation of 5-bromo-5-(4'-biphenyl)barbituric acid

A suspension of 5-(4'-biphenyl)barbituric acid (0.28 g) in 1.4 ml ofwater, cooled at 0° C. and kept under stirring, is added dropwise with0.14 ml of 48% hydrobromic acid and successively with 5 5.5 μl ofbromine. The temperature is then brought to room temperature and thestirring is continued for 1 hour. The suspended solid is recovered byfiltration, washed with water and dried under vacuum at 60° C. for 2hours, to give 0.336 of the product, m.p. 203-205° C.

e) Preparation of the Title Compound

To a suspension of 5-bromo-5-(4'-biphenyl)barbituric acid (0.323 g) in4.4 ml of ethanol 0.14 g of N-(2-hydroxyethyl)piperazine are added andthe reaction mixture is refluxed for 2 hours. The suspended solid isfiltered off and the resulting clear solution is treated with 125 μl oftriethylamine, then the solvent is evaporated off. The residue isredissolved in 2 ml of ethanol, from which crystallizes a solid which isstirred for 30 minutes, then it is filtered. The residue isrecrystallized from ethanol to give 100 mg of the pure product, m.p.225-226° C.

¹ H-NMR in d6-DMSO: 2.3-2.5 ppm (m, 6H); 2.65 ppm (m, 4H); 3.45 ppm (m,2H); 4.4 ppm (s, 1H); 7.3-7.8 ppm (m, 9H); 11.6 ppm (s, 2H).

EXAMPLE 26 5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinyl]barbituricacid

A solution of 5-bromo-5-(4'-biphenyl)barbituric acid (0.359 g; example25, step d) in 9 ml of methanol is added with 0.622 g ofN-(4-nitrophenyl)piperazine and the mixture is refluxed for about 2hours. The solvent is evaporated off and the residue is partitionedbetween water and ethyl acetate. The organic phase is separated, washedwith brine and dried over sodium sulfate. The solvent is then evaporatedunder reduced pressure to give 0.74 g of a residue which is purified bysilica gel chromatography (eluent: methylene chloride/acetone 9:1) togive 400 mg of the product, m.p. 181° C.

¹ H-NMR in d6-DMSO: 2.8 ppm (m, 4H); 3.5 ppm (m, 4H); 7.00 ppm (d, 2H);7.3-7.85 ppm (m, 9H); 8.05 ppm (d, 2H); 11.7 ppm (s, 2H).

EXAMPLE 275-(4'phenoxyphenyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid

a) Preparation of N-[(4'-phenoxybenzyl)thiocarbonyl]morpholine

A mixture of (4'-phenoxyphenyl)methylketone (19.1 g), morpholine (20 ml)and sulphur (4.32 g) is refluxed for 24 hours, then it is extracted withdiethyl ether. The organic phase is concentrated to dryness to give,after crystallization form a petroleum ether/ethyl acetate mixture 8:2(600 ml), 12.2 g of the product, m.p. 75-77° C.

b) Preparation of (4'-phenoxyphenyl)acetic acid

A suspension of N-[(4'-phenoxybenzyl)thiocarbonyl]morpholine (1.725 g)in 87 ml of 10% potassium hydroxide is refluxed for 8 hours 30 minutes,then the reaction mixture is brought to room temperature and acidifiedwith 1N hydrochloric acid. A white solid separates, which is stirred for30 minutes and filtered. The solid is washed with water and dried undervacuum to give 1.095 g of the product, m.p. 70-72° C.

c) Preparation of Ethyl (4'-phenoxyphenyl)acetate

To a suspension of (4'-phenoxyphenyl)acetic acid (0.456 g) in 4 ml ofethanol is added para-toluensulfonic acid (0.076 g) and the resultingmixture is refluxed for 2 hours. The solvent is evaporated off, theresidue is dissolved in diethyl ether and the organic phase is washedwith saturated aqueous solution of sodium hydrogencarbonate and thenwith brine. The organic phase is dried over sodium sulfate andconcentrated to dryness to give 0.458 g of the product as a brown oil.

d) Preparation of 5-(4'-phenoxyphenyl)barbituric acid

A solution of sodium ethoxide (0.27 g) in 3 ml of anhydrous ethanol isadded with 0.657 g of ethyl (4'-phenoxyphenyl)acetate dissolved in 5 mlof ethanol, then with urea (0.18 g). The reaction mixture is refluxedfor 2 hours 30 minutes, then it is cooled to room temperature and thesuspended solid is filtered. The solid is redissolved in 8 ml of waterand the solution is acidified with 1 N hydrochloric acid. The solidwhich separates is recovered by filtration to give 0. 165 g of theproduct, m.p. >240° C.

e) Preparation of 5-bromo-5-(4'-phenoxyphenyl)barbituric acid

To a suspension of 5-(4'-phenoxyphenyl)barbituric acid (48 mg)in 0.23 mlof water, cooled at 0° C. and under stirring, are added 23 μl of 48%hydrobromic acid and successively 9 μl of bromine. After 2 hours at roomtemperature additional 9 μl of bromine are added and stirring iscontinued for 2 hours. The suspended solid is then filtered and washedwith water, to give, after drying under vacuum at 60° C., 57 mg of theproduct, m.p. 125-127° C.

f) Preparation of the Title Compound

A solution of 5-bromo-5-(4'-phenoxyphenyl)barbituric acid (50 mg) in 0.2ml of methanol is added dropwise with a solution ofN-(2-hydroxyethyl)piperazine (52 mg) in 0.6 ml of methanol and themixture is stirred for 2 hours. The white precipitate is recovered byfiltration and dried under vacuum at 60° C. overnight. 42.6 mg of theproduct are obtained, m.p. >240° C.

¹ H-NMR in d6-DMSO: 2.2-2.45 ppm (m, 6H); 2.55 ppm (m, 4H); 3.45 ppm (m,2H); 4.4 ppm (t, 1H); 6.9-7.7 ppm (m, 9H); 11.6 ppm (s, 2H).

EXAMPLE 28 5-decyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid

a) Preparation of Diethyl Decylmalonate

A solution of sodium (0.46 g) in 10 of anhydrous ethanol is added with3.35 ml of diethyl malonate in 3 ml of ethanol and successively with asolution of decylbromide (4.15 ml) in 3 ml of ethanol. The reactionmixture is refluxed for 4 hours, then the precipitate is filtered offand the filtrate is concentrated to dryness. The residue is redissolvedin a saturated aqueous solution of sodium hydrogensulfate and it isextracted with ethyl acetate. The organic extract is dried over sodiumsulfate and the solvent is evaporated off. The resulting residue is usedas such in the successive reaction.

b) Preparation of 5-decylbarbituric acid

To a solution of diethyl decylmalonate of step a) in 40 ml of ethanolare added 2.72 g of sodium ethoxide and then 1.8 g of urea The reactionmixture is refluxed for 2 hours, then the precipitate is filtered andredissolved in 40ml of water. The resulting aqueous solution isacidified with 6 N hydrochloric acid. The solid which separates isrecovered by filtration and dried under vacuum at 40° C. overnight togive 2.152 g of the product, m.p. 190° C.

c) Preparation of 5-bromo-5-decylbarbituric acid

To a suspension of 5-decylbarbituric acid (0.537 g) in 2.9 ml of waterare added under stirring at room temperature 0.29 ml of 48% hydrobromicacid. The mixture is cooled to 0° C. and 0.113 ml of bromine aredropped. The reaction mixture is stirred at room temperature for 1 hour30 minutes. then the white precipitate is filtered and it is washed withwater. The solid is partitioned between water and diethyl ether, theorganic phase is separated, washed with brine and finally dried oversodium sulfate. By evaporation of the solvent under reduced pressure0.62 g of the product are recovered.

d) Preparation of the Title Compound

To a solution of 5-bromo-5-decylbarbituric acid (0.619 g) in 1.3 ml ofdimethylsulfoxide, kept under stirring at 0° C., a solution of 0.93 g ofN-(2-hydroxyethyl)piperazine in 0.7 ml of dimethylsulfoxide is addeddropwise, then the reaction mixture is stirred at room temperature for 1hour. The mixture is then cooled to 0° C. and added with 30 ml of water.A white solid separates, which is kept under stirring for 1 hour, thenis filtered and dried under vacuum at 50° C. 0.309 g of the product areobtained, m.p. 181-182° C.

¹ H-NMR in d6-DMSO: 0.85 ppm (t, 3H); 0.9-1.1 ppm (m, 2H); 1.15-1.4 ppm(m, 14H); 1.8-1.9 ppm (m, 2H); 2.2-2.45 ppm (m, 6H); 2.55 ppm (m, 4H);3.45 ppm (m, 2H); 4.35 ppm (t, 1H); 11.55 ppm (s, 2H).

EXAMPLE 29 5-hexdecyl-5-[N-(2-hydroxyethyl)piperazine]barbituric acid

The title compound was prepared in an analogous manner like the compoundof example 28.

EXAMPLE 30 5-eicoxyl-5-[N-(2-hydroxyethyl)piperazine]barbituric acid

The title compound was prepared in an analogous manner like the compoundof example 28.

EXAMPLE 31 5-(4-butoxyphenyl)-5-[4-(2-hdroxphenyl)piperazinyl]barbituricacid

m.p. 184-185°; H-N.M.R. in d6-DMSO: 0.91 ppm (t, 3H); 1.4 ppm (m, 2H);1.67 ppm (m, 2H); 2.36 ppm (m, 6H); 2.55 ppm (m, 4H; 3.44 ppm (q, 2H);3.95 ppm (t, 2H); 4.37 ppm (t, 1H); 6.95 ppm (d, 2H); 7.28 ppm (d, 2H);11.5 ppm (br. s, 2H).

The compound is prepared as described in Example 14. The only differenceis in the preparation of the starting material ethyl 4-butoxyphenylacetate, which can be prepared starting from 4-hydroxyphenylacetic acidby esterfication with ethanol (see example 14-a) and subsequenzalkylation of ethyl 4-hydroxyphenyl acetate with butyl bromidealkylation of ethyl 4-hydroxyphenyl acetate with butyl bromide,according to know methodologies.

EXAMPLE 32

The pathway of production as described in the specification andexamplified in the previous examples the following compounds aresynthesized. They are characterized by mass spectroscopy.

    ______________________________________                                        32.                                   exp.                                      xx Name MW mass                                                             ______________________________________                                        01  N-(2,4,6-Trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)-                                                      323.3  323                                        benzamide                                                                    02 3-(3,4-Dimethoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl- 409.4 409                                                     hexahydro-pyrimidin-5-yl)-acrylami                                          de                                        03 3-(3,4,5-Trimethoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl- 439.4 439                                                  hexahydro-pyrimidin-5-yl)-acrylami                                          de                                        04 3-Phenyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 351.4 351                      pyrimidin-5-yl)-propionamide                                                 05 5-Phenyl-pentanoic acid (2,4,6-trioxo-5-phenyl- 379.4 379                   hexahydro-pyrimidin-5-yl)-amide                                              06 2-(4-Nitro-phenyl)-N-(2,4,6-trioxo-5-phenyl- 382.3 382                      hexahydro-pyrimidin-5-yl)-acetamide                                          07 3-Benzenesulfonyl-N-(2,4,6-trioxo-5-phenyl- 415.4 415                       hexahydro-pyrimidin-5-yl)-propionamide                                       08 2-(4-Bromomethyl-phenyl)-N-(2,4,6-trioxo-5-phenyl- 430.3 429                                                     hexahydro-pyrimidin-5-yl)-acetamid                                          e                                         09 2-Naphthalen-2-yl-N-(2,4,6-trioxo-5-phenyl- 387.4 387                       hexahydro-pyrimidin-5-yl)-acetamide                                          10 2-(3-Chloro-phenyl)-N-(2,4,6-trioxo-5-phenyl- 371.8 371                     hexahydro-pyrimidin-5-yl)-acetamide                                          11 3-(2-Methoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl- 381.4 381                    hexahydro-pyrimidin-5-yl)-propionamide                                       12 3-(4-Methoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl- 381.4 381                    hexahydro-pyrimidin-5-yl)-propionamide                                       13 2-(3-Bromo-phenyl)-N-(2,4,6-trioxo-5-phenyl- 416.2 415                      hexahydro-pyrimidin-5-yl)-acetamide                                          14 3-Phenyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 349.3 349                      pyrimidin-5-yl)-acrylamide                                                   15 4-Bromo-N-(2,4,6-trioxo-5-phenyl-hexahydro- 402.2 401                       pyrimidin-5-yl)-benzamide                                                    16 3-Methyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 337.3 337                      pyrimidin-5-yl)-benzamide                                                    17 4-Methylsulfanyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 369.4 369                                                   pyrimidin-5-yl)-benzamide                                                    18 3-Chloro-N-(2,4,6-trioxo-5-pheny                                          l-hexahydro- 357.8 357                     pyrimidin-5-yl)-benzamide                                                    19 4-Chloro-N-(2,4,6-trioxo-5-phenyl-hexahydro- 357.8 357                      pyrimidin-5-yl)-benzamide                                                    20 3,4-Dimethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 351.4 351                  pyrimidin-5-yl)-benzamide                                                    21 3,5-Dimethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 351.4 351                  pyrimidin-5-yl)-benzamide                                                    22 4-Ethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 367.4 367                      pyrimidin-5-yl)-benzamide                                                    23 4-Cyano-N-(2,4,6-trioxo-5-phenyl-hexahydro- 348.3 348                       pyrimidin-5-yl)-benzamide                                                    24 3-Methoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 353.3 353                     pyrimidin-5-yl)-benzamide                                                    25 4-Methoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 353.3 353                     pyrimidin-5-yl)-benzamide                                                    26 2-Methyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 337.3 337                      pyrimidin-5-yl)-benzamide                                                    27 2,4-Difluoro-N-(2,4,6-trioxo-5-phenyl-hexahydro- 359.3 359                  pyrimidin-5-yl)-benzamide                                                    28 N-(2,4,6-Trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)- 324.3 324                                                    isonicotinamide                         29 Naphthalene-1-carboxylic acid (2,4,6-trioxo-5-phenyl- 373.4 373                                                  hexahydro-pyrimidin-5-yl)-amide                                              30 1-(4-Fluoro-phenyl)-3-(2,4,6-tri                                          oxo-5-phenyl- 356.3 356                    hexahydro-pyrimidin-5-yl)-urea                                               31 3-(4-Methoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl- 379.4 379                    hexahydro-pyrimidin-5-yl)-acrylamide                                         32 1-(3-Trifluoromethyl-phenyl)-3-(2,4,6-trioxo-5-phenyl- 406.3 406                                                 hexahydro-pyrimidin-5-yl)-urea                                               33 3-(4-Chloro-phenyl)-N-(2,4,6-tri                                          oxo-5-phenyl- 383.8 383                    hexahydro-pyrimidin-5-yl)-acrylamide                                         34 1-(2,4-Dichloro-phenyl)-3-(2,4,6-trioxo-5-phenyl- 407.2 406                 hexahydro-pyrimidin-5-yl)-urea                                               35 1-(3,4-Dichloro-phenyl)-3-(2,4,6-trioxo-5-phenyl- 407.2 406                 hexahydro-pyrimidin-5-yl)-urea                                               36 1-(Chlor-phenyl)-3-(2,4,6-trioxo-5-phenyl-hexahydro- 372.7 372                                                   pyrimidin-5-yl)-urea                    37 1-(4-Methoxy-phenyl)-3-(2,4,6-trioxo-5-phenyl- 368.4 368                    hexahydro-pyrimidin-5-yl)-urea                                               38 1-Phenyl-3-(2,4,6-trioxo-5-phenyl-hexahydro- 338.3 338                      pyrimidin-5-yl)-urea                                                         39 Naphthalene-2-carboxylic acid (2,4,6-trioxo-5-phenyl- 373.4 373                                                  hexahydro-pyrimidin-5-yl)-amide                                              40 1H-Indole-5-carboxylic acid                                               (2,4,6-trioxo-5-phenyl- 362.3 362                                               hexahydro-pyrimidin-5-yl)-amide                                              41 N-(2,4,6-Trioxo-5-phenyl-hexahyd                                          ro-pyrimidin-5-yl)- 366.3 366                                                   terephthalamide                         42 4-Sulfamoyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 402.4 402                   pyrimidin-5-yl)-benzamide                                                    43 4-Methyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 337.3 337                      pyrimidin-5-yl)-benzamide                                                    44 4-Ethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 351.4 351                       pyrimidin-5-yl)-benzamide                                                    45 4-Methyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 373.4 373                      pyrimidin-5-yl)-benzenesulfonamide                                           46 4-Bromo-N-(2,4,6-trioxo-5-phenyl-hexahydro- 438.3 437                       pyrimidin-5-yl)-benzenesulfonamide                                           47 2-Trifluoromethyl-N-(2,4,6-trioxo-5-phenyl- 427.4 427                       hexahydro-pyrimidin-5-yl)-benzenesulfonamide                                 48 5-Phenyl-5-(4-phenyl-piperidin-1-yl)-pyrimidine-2,4,6- 363.4 363                                                 trione                                  49 2,3-Dimethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 383.4 383                 pyrimidin-5-yl)-benzamide                                                    50 2,3-Dimethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 351.4 351                  pyrimidin-5-yl)-benzamide                                                    51 4-Hydroxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 339.3 411                     pyrimidin-5-yl)-benzamide  silyl.                                            52 3,4-Dimethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 383.4 383                 pyrimidin-5-yl)-benzamide                                                    53 3-Dimethylamino-N-(2,4,6-trioxo-5-phenyl-hexahydro- 366.4 366                                                    pyrimidin-5-yl)-benzamide                                                    54 3-tert-Butyl-N-(2,4,6-trioxo-5-p                                          henyl-hexahydro- 379.4 379                 pyrimidin-5-yl)-benzamide                                                    55 3,4-Dimethoxy-2-nitro-N-(2,4,6-trioxo-5-phenyl- 428.4 428+                  hexahydro-pyrimidin-5-yl)-benzamide  FAB                                     56 4-Butoxy-3-methoxy-N-(2,4,6-trioxo-5-phenyl- 425.4 425+                     hexahydro-pyrimidin-5-yl)-benzamide  FAB                                     57 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid 379.4 379+                                                     (2,4,6-trioxo-5-phenyl-hexahydro-p                                          yrimidin-5-yl)-  FAB                       amide                                                                        58 1H-Indol-4-carboxylic acid (2,4,6-trioxo-5-phenyl- 362.3 362                                                     hexahydro-pyrimidin-5-yl)-amide                                              59 4-Methyl-3-sulfamoyl-N-(2,4,6-tr                                          ioxo-5-phenyl- 416.4 416                   hexahydro-pyrimidin-5-yl)-benzamide                                          60 Acetic acid 6-methyl-2-nitro-3-(2,4,6-trioxo-5-phenyl- 440.4 440+                                                hexahydro-pyrimidin-5-ylcarbamoyl)                                          -phenyl ester  FAB                        61 Carbonic acid ethyl ester 2-methoxy-4-(2,4,6-trioxo-5- 441.4 441+                                                phenyl-hexahydro-pyrimidin-5-ylcar                                          bamoyl)-phenyl FAB                         ester                                                                        62 2-Bromo-3-nitro-N-(2,4,6-trioxo-5-phenyl-hexahydro- 447.2 446                                                    pyrimidin-5-yl)-benzamide                                                    63 "4-Chloro-3-sulfamoyl-N-(2,4,6-t                                          rioxo-5-phenyl- 436.8 436                  hexahydro-pyrimidin-5-yl)-benzamide e"                                       65 3-tert-Butyl-2-hydroxy-N-(2,4,6-trioxo-5-phenyl- 395.4 395                  hexahydro-pyrimidin-5-yl)-benzamide                                          66 4'-Benzyloxy-biphenyl-3-carboxylic acid 505.5 505+                          (2,4,6-trioxo-5-phenyl-hexahydro-pyrimidein-5-yl)-  FAB                       amide                                                                        67 3-Cyano-N-(2,4,6-trioxo-5-phenyl-hexahydro- 348.3 348                       pyrimidin-5-yl)-benzamide                                                    68 3-Bromo-N-(2,4,6-trioxo-5-phenyl-hexahydro- 402.2 401                       pyrimidin-5-yl)-benzamide                                                    69 3-Phenoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 415.4 415+                    pyrimidin-5-yl)-benzamide  FAB                                               70 3-Benzoyl-N-(2,4,6-trioxo-5-phenyl-hexahydro- 427.4 427                     pyrimidin-5-yl)-benzamide                                                    71 3-Trifluoromethyl-N-(2,4,6-trioxo-5-phenyl- 391.3 391                       hexahydro-pyrimidin-5-yl)-benzamide                                          72 N-(2,4,6-Trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)- 381.3 381                                                    isophthalamic acid methyl ester                                              73 9H-Fluorene-1-carboxylic acid                                             (2,4,6-trioxo-5-phenyl- 411.4 411                                               hexahydro-pyrimidin-5-yl)-amide                                              74 9-Oxo-9H-fluorene-1-carboxylic                                            acid (2,4,6-trioxo-5- 425.4 425                                                 phenyl-hexahydro-pyrimidin-5-yl)-a                                          mide                                      75 5-Phenyl-5-(4-phenyl-piperazin-1-yl)-pyrimidine- 364.4 364                  2,4,6-trione                                                                 76 5-Phenyl-5-[4-(2-trifluoromethyl-phenyl)-piperazin-1- 432.4 432                                                  yl]-pyrimidine-2,4,6-trione                                                  77 5-[4-(4-Nitro-phenyl)-piperazin-                                          1-yl]-5-phenyl- 409.4 409                  pyrimidine-2,4,6-trione                                                      78 5-(4-Phenethyl-piperazin-1-yl)-5-phenyl-pyrimidine- 392.5 392                                                    2,4,6-trione                            79 5-[4-(3-Methoxy-phenyl)-piperazin-1-yl]-5-phenyl- 394.4 394                 pyrimidine-2,4,6-trione                                                      80 3-Acetylamino-N-(2,4,6-trioxo-5-phenyl-hexahydro- 380.4 380                 pyrimidin-5-yl)-benzamide                                                    81 Acetic acid 3-(2,4,6-trioxo-5-phenyl-hexahydro- 381.3 381                   pyrimidin-5-ylcarbamoyl)-phenyl ester                                        82 3-Ethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro- 367.4 367                      pyrimidin-5-yl)-benzamide                                                    83 5-Phenyl-5-(4-pyridin-4-yl-piperazin-1-yl)- 365.4 365                       pyrimidine-2,4,6-trione                                                      84 5-Phenyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-1- 432.4 432                                                  yl]-pyrimidine-2,4,6-trione                                                  85 5-[4-(4-Methoxy-phenyl)-piperazi                                          n-1-yl]-5-phenyl- 394.4 394                                                     pyrimidine-2,4,6-trione                 86 5-(4-Benzhydryl-piperazin-1-yl)-5-phenyl-pyrimidine- 454.5 454+                                                  2,4,6-trione  FAB                       87 5-Phenyl-5-[4-(3-phenyl-allyl)-piperazin-1-yl]- 404.5 404+                  pyrimidine-2,4,6-trione  FAB                                                 88 5-Phenyl-5-(2-pyrrolidin-1-yl-ethylamino)-pyrimidine- 316.4 316                                                  2,4,6-trione                            89 5-[2-(3H-Imidazol-4-yl)-ethylamino]-5-phenyl- 313.3 313+                    pyrimidine-2,4,6-trione  FAB                                               ______________________________________                                    

EXAMPLE 33

In order to determine the inhibition of MMPs, for example HNC, thecatalytic domain (isolation and purification see for example Schnierer,S., Kieine, T., Gote, T., Hiliemann, A., Knauper, V., Tschesche, H.,Biochem. Biophys. Res. Commun. (1993) 191, 319-326) is incubated withinhibitors having various concentrations. Subsequently, the initialreaction rate in the conversion of a standard substrate is measured in amanner analogous to Grams F. et al., FEBS 335 (1993) 76-80).

The results are evaluated by plotting the reciprocal reaction rateagainst the concentration of the inhibitor. The inhibition constant (Ki)is obtained as the negative section of the abscissis by the graphicalmethod according to Dixon, M. Biochem. J. (1953) 55, 170-202.

The synthetic collagenase substrate is a heptapeptide which is coupled,at the C-terminus, with DNP (dinitrophenol). Said DNP residue quenchesby steric hindrance the fluorescence of the adjacent tryptophane of theheptapeptide. After cleavage of a tripeptide which includes the DNPgroup, the tryptophane fluorescence increases. The proteolytic cleavageof the substrate therefore can be measured by the fluorescence value.

a) First Method

The assay was performed at 25° C. in a freshly prepared 50 mM Trisbuffer (pH 8.0) treated with dithiozone to remove traces of heavymetals. 4 mM CaCl₂ was added and the buffer saturated wtih argon. Stocksolutions of adamalysin II were prepared by centrifugation of theprotein from an ammonium sulfate suspension and subsequent dissolutionin the assay buffer. Stock solutions of collagenase were diluted withthe assay buffer. Enzyme concentrations were determined by uvmeasurements (ε₂₈₀ =2.8 10⁴ M⁻ 1 cm⁻¹, ε₂₈₈ : 2.2 10⁴ M⁻¹ cm⁻¹) and thestock solutions were stored in the cold. This solution was diluted 1:100to obtain the final 16 nM assay concentration. The fluorogenic substrateDNP-ProLeu-Gly-LeuTrp-Ala-D-Arg-NH₂ with a K_(m) of 52 μM was used at aconcentration of 21.4 μM; for the K_(i) determination a 12.8 μMconcentration has also been used. Substrate fluorescence was measured atan excitation and emission wavelength of λ=320 and 420 nm, respectively,on a spectrofluorimeter (Perkin Elmer, Model 650-40) equipped with athennostated cell holder. Substrate hydrolysis was monitored for 10 min.immediately after adding the enzyme. All reactions were performed atleast in triplicate. The K_(i) values-of the inhibitors were calculatedfrom the intersection point of the straight lines obtained by the plotsof v_(o) /v_(i) vs. [concentration of inhibitor], whereas 1C₅₀ valueswere calculated from plots of v_(i) /v_(o) [concentration of inhibitor]by non-linear regression with simple robust weighting.

b) Second Method

Assay buffer:

50 mM Tris/HCl pH 7.6 (Tris=Tris-(hydroxymethyl)aminomethan)

100 mM NaCl/10 mM CaCl2/5% MEOH (ff necessary)

Enzyme: 8 nM catalytic domain (Met80-Gly242) of human neutrophilcollagenase

Substrate: 10 microM DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg--NH2 Total assayvolume: 1 ml

A solution of the enzyme and inhibitor in assay buffer (25° C.) wasprepared. The reaction was started directly by giving the substrate intothe solution. The cleavage of the flourogenic substrate was followed byflourescence spectroscopy with an excitation and emission wavelength of280 and 350 nm, respectively. The IC₅₀ value was calculated as theinhibitor concentration, which is necessary to decrease the velocity ofthe reaction to the half in comparison to the reaction withoutinhibitor.

Table 1 shows the IC₅₀ values found.

                  TABLE 1                                                         ______________________________________                                        IC50 Values of MMP-Inhibitor (MMP-8                                                   Compound    IC-50 [nM]                                                ______________________________________                                        example 32.74   890                                                             preferred no. 120 150                                                         example 25 140                                                                example 23 110                                                                example 20 860                                                                example 32.77 160                                                             preferred no 118  60                                                          example 28 320                                                                example 26  15                                                              ______________________________________                                    

What is claimed is:
 1. A compound of formula I ##STR8## wherein X, Y andZ are each oxygen;R₁ is selected from the group consisting of (a)n-octyl, (b) n-decyl, (c) biphenyl and (d) (4-phenoxy)phenyl, whereinthe terminal monocycle for moieties (c)-(d) is unsubstituted orsubstituted by a substituent selected from the group consisting of--NH₂, --NO₂, --SO₂ NH₂, --SO₂ CH₃, acetyl, hydroxy, methoxy, ethoxy,cyano and halogen; R₂ and R₃ are each hydrogen; and R₄ and R₅, togetherwith the nitrogen atom to which they are bound, form a piperazinyl orpiperidyl ring, wherein the piperazinyl ring is substituted in the4-position with a substituent selected from the group consisting of (a)a 6-membered aromatic monocycle having 0, 1 or 2 nitrogen atoms and theremainder of the atoms in the monocycle being carbon and (b) hydroxy-C₁-C₆ alkyl, wherein the monocycle is unsubstituted or substituted by asubstituent selected from the group consisting of halogen, --NH₂, --NO₂,--SO₂ NH₂, --SO₂ CH₃, acetyl and cyano.
 2. The compound of claim 1,wherein the 6-membered aromatic monocycle is selected from the groupconsisting of phenyl, pyridyl and pyrazinyl.
 3. The compound of claim 1,wherein the compound is selected from the group consistingof5-octyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid;5-(4'-biphenyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid;5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid;5-decyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid; and5-[4-(4-nitrophenyl)piperazinyl]-5-octyl-barbituric acid.
 4. Thecompound of claim 1, wherein the compound is5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid.
 5. Apharmaceutical composition suitable for use as a matrix metalloproteaseinhibitor, comprising a compound of claim 1 in combination with apharmaceutically acceptable carrier.
 6. A method of inhibiting a matrixmetalloprotease in a patient in need of such inhibition, comprisingadministering to the patient a matrix metalloproteaseinhibiting-effective amount of a compound of formula I ##STR9## whereinX, Y and Z are each oxygen;R₁ is selected from the group consisting of(a) n-octyl, (b) n-decyl, (c) biphenyl and (d) (4-phenoxy)phenyl,wherein the terminal monocycle for moieties (c)-(d) is unsubstituted orsubstituted by a substituent selected from the group consisting of--NH₂, --NO₂, --SO₂ NH₂, --SO₂ CH₃, acetyl, hydroxy, methoxy, ethoxy,cyano and halogen; R₂ and R₃ are each hydrogen; and R₄ and R₅, togetherwith the nitrogen atom to which they are bound, form a piperazinyl orpiperidyl ring, wherein the piperazinyl ring is substituted in the4-position with a substituent selected from the group consisting of (a)a 6-membered aromatic monocycle having 0, 1 or 2 nitrogen atoms and theremainder of the atoms in the monocycle being carbon and (b) hydroxy-C₁-C₆ alkyl, wherein the monocycle is unsubstituted or substituted by asubstituent selected from the group consisting of halogen, --NH₂, --NO₂,--SO₂ NH₂, --SO₂ CH₃, acetyl and cyano, or a pharmaceutically acceptablesalt or optically active isomer thereof.
 7. The method of claim 6,wherein the 6-membered aromatic monocycle is selected from the groupconsisting of phenyl, pyridyl and pyrazinyl.
 8. The method of claim 6,wherein the compound is selected from the group consistingof5-octyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid;5-(4'-biphenyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid;5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid;5-decyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid; and5-[4-(4-nitrophenyl)piperazinyl]-5-octyl-barbituric acid.
 9. The methodof claim 6, wherein the compound is5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid.
 10. Amethod of treating a pathological condition associated with excessivematrix metalloprotease activity in a patient in need of such treatment,comprising administering to the patient a pathological conditiontreating-effective amount of a compound of formula I ##STR10## whereinX, Y and Z are each oxygen;R₁ is selected from the group consisting of(a) n-octyl, (b) n-decyl, (c) biphenyl and (d) (4-phenoxy)phenyl,wherein the terminal monocycle for moieties (c)-(d) is unsubstituted orsubstituted by a substituent selected from the group consisting of--NH₂, --NO₂, --SO₂ NH₂, --SO₂ CH₃, acetyl, hydroxy, methoxy, ethoxy,cyano and halogen; R₂ and R₃ are each hydrogen; and R₄ and R₅, togetherwith the nitrogen atom to which they are bound, form a piperazinyl orpiperidyl ring, wherein the piperazinyl ring is substituted in the4-position with a substituent selected from the group consisting of (a)a 6-membered aromatic monocycle having 0, 1 or 2 nitrogen atoms and theremainder of the atoms in the monocycle being carbon and (b) hydroxy-C₁-C₆ alkyl, wherein the monocycle is unsubstituted or substituted by asubstituent selected from the group consisting of halogen, --NH₂, --NO₂,--SO₂ NH₂, --SO₂ CH₃, acetyl and cyano, or a pharmaceutically acceptablesalt or optically active isomer thereof.
 11. The method of claim 10,wherein the pathological condition is selected from the group consistingof rheumatoid arthritis, osteoarthritis and multiple sclerosis.
 12. Themethod of claim 10, wherein the 6-membered aromatic monocycle isselected from the group consisting of phenyl, pyridyl and pyrazinyl. 13.The method of claim 10, wherein the compound is selected from the groupconsisting of5-octyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid;5-(4'-biphenyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid;5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid;5-decyl-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid; and5-[4-(4-nitrophenyl)piperazinyl]-5-octyl-barbituric acid.
 14. The methodof claim 10, wherein the compound is5-(4'-biphenyl)-5-[N-(4-methylphenyl)piperazinyl]barbituric acid.